Heterocyclic modulators of nuclear receptors

ABSTRACT

Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of farnesoid X receptor (FXR), liver X receptor (LXR) and/or orphan nuclear receptors. In certain embodiments, the compounds are thiazolidinone derivatives.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/329,668, filed Dec. 20, 2002, now U.S. Pat. No. 6,696,473 to Martinet al., entitled “HETEROCYCLIC MODULATORS OF NUCLEAR RECEPTORS,” whichclaims the benefit of priority under 35 U.S.C. 119(e) to U.S.Provisional Patent Application No. 60/342,720, filed Dec. 21, 2001, toMartin et al., entitled “HETEROCYCLIC MODULATORS OF NUCLEAR RECEPTORS.”The disclosures of the above-referenced applications are incorporated byreference herein in their entirety.

FIELD

Compounds, compositions and methods for modulating the activity ofnuclear receptors are provided. In particular, heterocyclic compoundsare provided for modulating the activity of orphan nuclear receptors.

BACKGROUND

Nuclear Receptors

Nuclear receptors are a superfamily of regulatory proteins that arestructurally and functionally related and are receptors for, e.g.,steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans(1988) Science 240:889–895). These proteins bind to cis-acting elementsin the promoters of their target genes and modulate gene expression inresponse to ligands for the receptors.

Nuclear receptors can be classified based on their DNA bindingproperties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev.15:391–407). For example, one class of nuclear receptors includes theglucocorticoid, estrogen, androgen, progestin and mineralocorticoidreceptors which bind as homodimers to hormone response elements (HREs)organized as inverted repeats (see, e.g., Glass, supra). A second classof receptors, including those activated by retinoic acid, thyroidhormone, vitamin D₃, fatty acids/peroxisome proliferators (i.e.,peroxisome proliferator activated receptor (PPAR)) and ecdysone, bind toHREs as heterodimers with a common partner, the retinoid X receptors(i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g.,Levin et al. (1992) Nature 355:359–361 and Heyman et al. (1992) Cell68:397–406).

RXRs are unique among the nuclear receptors in that they bind DNA as ahomodimer and are required as a heterodimeric partner for a number ofadditional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al.(1995) Cell 83:841–850). The latter receptors, termed the class IInuclear receptor subfamily, include many which are established orimplicated as important regulators of gene expression. There are threeRXR genes (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329–344),coding for RXRα, -β, and -γ, all of which are able to heterodimerizewith any of the class II receptors, although there appear to bepreferences for distinct RXR subtypes by partner receptors in vivo (see,e.g., Chiba et al. (1997) Mol. Cell. Biol. 17:3013–3020). In the adultliver, RXRα is the most abundant of the three RXRs (see, e.g.,Mangelsdorf et al. (1992) Genes Dev. 6:329–344), suggesting that itmight have a prominent role in hepatic functions that involve regulationby class II nuclear receptors. See also, Wan et al. (2000) Mol. Cell.Biol. 20:4436–4444.

Orphan Nuclear Receptors

Included in the nuclear receptor superfamily of regulatory proteins arenuclear receptors for whom the ligand is known and those which lackknown ligands. Nuclear receptors falling in the latter category arereferred to as orphan nuclear receptors. The search for activators fororphan receptors has led to the discovery of previously unknownsignaling pathways (see, e.g., Levin et al., (1992), supra and Heyman etal., (1992), supra). For example, it has been reported that bile acids,which are involved in physiological processes such as cholesterolcatabolism, are ligands for FXR (infra).

Since it is known that products of intermediary metabolism act astranscriptional regulators in bacteria and yeast, such molecules mayserve similar functions in higher organisms (see, e.g., Tomkins (1975)Science 189:760–763 and O'Malley (1989) Endocrinology 125:1119–1120).For example, one biosynthetic pathway in higher eukaryotes is themevalonate pathway, which leads to the synthesis of cholesterol, bileacids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitaminD, steroid hormones and farnesylated proteins.

FXR

FXR (originally isolated as RIP14 (retinoid X receptor-interactingprotein-14), see, e.g., Seol et al. (1995) Mol. Endocrinol. 9:72–85) isa member of the nuclear hormone receptor superfamily and is primarilyexpressed in the liver, kidney and intestine (see, e.g., Seol et al.,supra and Forman et al. (1995) Cell 81:687–693). It functions as aheterodimer with the retinoid X receptor (RXR) and binds to responseelements in the promoters of target genes to regulate genetranscription. The FXR-RXR heterodimer binds with highest affinity to aninverted repeat-1 (IR-1) response element, in which consensusreceptor-binding hexamers are separated by one nucleotide. FXR is partof an interrelated process, in that FXR is activated by bile acids (theend product of cholesterol metabolism) (see, e.g., Makishima et al.(1999) Science 284:1362–1365, Parks et al. (1999) Science 284:1365–1368,Wang et al. (1999) Mol. Cell. 3:543–553), which serve to inhibitcholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem.275:39313–39317.

LXRα and LXRβ

LXRα is found predominantly in the liver, with lower levels found inkidney, intestine, spleen and adrenal tissue (see, e.g., Willy, et al.(1995) Gene Dev. 9(9):1033–1045). LXRβ, also known as UR (ubiquitousreceptor), is ubiquitous in mammals and was found in nearly all tissuesexamined. LXRs are activated by certain naturally occurring, oxidizedderivatives of cholesterol (see, e.g., Lehmann, et al. (1997) J. Biol.Chem. 272(6):3137–3140). LXRα is activated by oxycholesterol andpromotes cholesterol metabolism (Peet et al. (1998) Cell 93:693–704).Thus, LXRs appear to play a role in, e.g., cholesterol metabolism (see,e.g., Janowski, et al. (1996) Nature 383:728–731).

Nuclear Receptors and Disease

Nuclear receptor activity has been implicated in a variety of diseasesand disorders, including, but not limited to, hypercholesterolemia (see,e.g., International Patent Application Publication No. WO 00/57915),osteoporosis and vitamin deficiency (see, e.g., U.S. Pat. No.6,316,5103), hyperlipoproteinemia (see, e.g., International PatentApplication Publication No. WO 01/60818), hypertriglyceridemia,lipodystrophy, peripheral occlusive disease, ischemic stroke,hyperglycemia and diabetes mellitus (see, e.g., International PatentApplication Publication No. WO 01/82917), atherosclerosis and gallstones(see, e.g., International Patent Application Publication No. WO00/37077), disorders of the skin and mucous membranes (see, e.g., U.S.Pat. Nos. 6,184,215 and 6,187,814, and International Patent ApplicationPublication No. WO 98/32444), acne (see, e.g., International PatentApplication Publication No. WO 00/49992), and cancer, Parkinson'sdisease and Alzheimer's disease (see, e.g., International PatentApplication Publication No. WO 00/17334). Activity of nuclear receptors,including FXR, LXRs and/or orphan nuclear receptors, has been implicatedin physiological processes including, but not limited to, bile acidbiosynthesis, cholesterol metabolism or catabolism, and modulation ofcholesterol 7α-hydroxylase gene (CYP7A1) transcription (see, e.g.,Chiang et al. (2000) J. Biol. Chem. 275:10918–10924), HDL metabolism(see, e.g., Urizar et al. (2000) J. Biol. Chem. 275:39313–39317),hyperlipidemia, cholestasis, and increased cholesterol efflux andincreased expression of ATP binding cassette transporter protein (ABC1)(see, e.g., International Patent Application Publication No. WO00/78972).

Thus, there is a need for compounds, compositions and methods ofmodulating the activity of nuclear receptors, including FXR, LXRs and/ororphan nuclear receptors. Such compounds are useful in the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders in which nuclear receptor activity is implicated.

SUMMARY

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating farnesoid X receptor(FXR), liver X receptors (LXRα and LXRβ) and/or orphan nuclearreceptors, are provided. In certain embodiments, the compounds areheterocyclic compounds that are substituted with a heterocyclylene groupand an imine moiety. In one embodiment, the compounds provided hereinare agonists of FXR and/or LXR. In another embodiment, the compoundsprovided herein are antagonists of FXR and/or LXR. Agonists that exhibitlow efficacy are, in certain embodiments, antagonists.

In one embodiment, the compounds for use in the compositions and methodsprovided herein have formulae I:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

-   -   (i) A and G are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted cycloalkylalkyl,        substituted or unsubstituted heterocyclylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroaralkyl, substituted or unsubstituted        heteroarylium, substituted or unsubstituted heteroaryliumalkyl,        halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and        C(=J)R¹³, or A and G together form substituted or unsubstituted        alkylene, substituted or unsubstituted azaalkylene, substituted        or unsubstituted oxaalkylene, substituted or unsubstituted        thiaalkylene, substituted or unsubstituted alkenylene,        substituted or unsubstituted alkynylene, substituted or        unsubstituted 1,3-butadienylene, substituted or unsubstituted        1-aza-1,3-butadienylene, or substituted or unsubstituted        2-aza-1,3-butadienylene;        -   D and E are each independently selected from hydrogen,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted heterocyclyl, substituted or unsubstituted            cycloalkylalkyl, substituted or unsubstituted            heterocyclylalkyl, substituted or unsubstituted aryl,            substituted or unsubstituted heteroaryl, substituted or            unsubstituted aralkyl, substituted or unsubstituted            heteroaralkyl, halo and pseudohalo or D and E together form            a bond; or    -   (ii) A and D; or E and G; together form substituted or        unsubstituted alkylene, substituted or unsubstituted        azaalkylene, substituted or unsubstituted oxaalkylene, or        substituted or unsubstituted thiaalkylene;    -   and the others of A, D, E and G are selected as in (i);

X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se,NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(=J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(=J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstitutedor substituted with one or more substituents, in one embodiment one tothree or four substituents, each independently selected from Q¹, whereQ¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; and

each Q¹ is independently unsubstituted or substituted with one or moresubstituents, in one embodiment one, two or three substituents, eachindependently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene;

each Q² is independently unsubstituted or substituted with one or more,in one embodiment one, two or three, substituents each independentlyselected from alkyl, halo and pseudohalo;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl; and

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae I:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

-   -   (i) A and G are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted cycloalkylalkyl,        substituted or unsubstituted heterocyclylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroaralkyl, substituted or unsubstituted        heteroarylium, substituted or unsubstituted heteroaryliumalkyl,        halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and        C(=J)R¹³, or A and G together form substituted or unsubstituted        alkylene, substituted or unsubstituted azaalkylene, substituted        or unsubstituted oxaalkylene, substituted or unsubstituted        thiaalkylene, substituted or unsubstituted alkenylene,        substituted or unsubstituted alkynylene, substituted or        unsubstituted 1,3-butadienylene, substituted or unsubstituted        1-aza-1,3-butadienylene, or substituted or unsubstituted        2-aza-1,3-butadienylene;        -   D and E are each independently selected from hydrogen,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted heterocyclyl, substituted or unsubstituted            cycloalkylalkyl, substituted or unsubstituted            heterocyclylalkyl, substituted or unsubstituted aryl,            substituted or unsubstituted heteroaryl, substituted or            unsubstituted aralkyl, substituted or unsubstituted            heteroaralkyl, halo and pseudohalo or D and E together form            a bond; or    -   (ii) A and D; or E and G; together form substituted or        unsubstituted alkylene, substituted or unsubstituted        azaalkylene, substituted or unsubstituted oxaalkylene, or        substituted or unsubstituted thiaalkylene;    -   and the others of A, D, E and G are selected as in (i);

X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se,NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(=J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(=J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstitutedor substituted with one or more substituents, in one embodiment one tothree or four substituents, each independently selected from Q¹, whereQ¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; and

each Q¹ is independently unsubstituted or substituted with one or moresubstituents, in one embodiment one, two or three substituents, eachindependently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl; and

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In certain embodiments herein, the compounds are selected with theproviso that when R³ is substituted or unsubstituted heteroarylium thenthe heteroatom substituent is not alkyl or aryl. In another embodiment,the compounds are selected with the proviso that R³ is not substitutedor unsubstituted heteroarylium or substituted or unsubstitutedheteroaryliumalkyl. In other embodiments, the compounds are selectedwith the proviso that R³ is not heteroaryl. In further embodiments, thecompounds are selected with the proviso that R³ is not alkyl. In anotherembodiment, the compounds are selected with the proviso that R³ is notheterocycloaryl (i.e., an aryl group possessing a fused heterocyclicmoiety).

The groups A, D, E, G, X¹, X², X³, R¹, R² and R³ are selected such thatthe resulting compound has nuclear receptor modulation activity, such asin at least one assay described herein, such as FXR antagonist oragonist activity, and, in certain embodiments, at an IC₅₀ or EC₅₀ ofless than about 100 μM. The FXR IC₅₀ or EC₅₀ values for the compoundsprovided herein are, in certain embodiments, less than about 50 μM, 25μM, 10 μM, 1 μM, 100 nM, 10 nM or 1 nM.

Also of interest are any pharmaceutically-acceptable derivatives,including salts, esters, enol ethers, enol esters, solvates, hydratesand prodrugs of the compounds described herein.Pharmaceutically-acceptable salts, include, but are not limited to,amine salts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc, aluminum, and other metal salts, such as but not limited tosodium hydrogen phosphate and disodium phosphate; and also including,but not limited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically acceptablederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders that are modulated or otherwise affected by nuclear receptoractivity, including FXR, LXR and/or orphan nuclear receptor activity, orin which nuclear receptor activity, including FXR, LXR and/or orphannuclear receptor activity, is implicated, are also provided. Theeffective amounts and concentrations are effective for ameliorating anyof the symptoms of any of the diseases or disorders.

Methods for treatment, prevention, or amelioration of one or moresymptoms of diseases or disorders mediated by or in which nuclearreceptor activity, including FXR, LXR and/or orphan nuclear receptoractivity, is implicated, are provided. Such methods include methods oftreatment, prevention and amelioration of one or more symptoms ofhypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia,lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia,atherosclerosis, gallstone disease, acne vulgaris, acneiform skinconditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease,inflammation, immunological disorders, lipid disorders, obesity,conditions characterized by a perturbed epidermal barrier function,hyperlipidemia, cholestasis, peripheral occlusive disease, ischemicstroke, conditions of disturbed differentiation or excess proliferationof the epidermis or mucous membrane, or cardiovascular disorders, usingone or more of the compounds provided herein, or pharmaceuticallyacceptable derivatives thereof.

Methods of modulating the activity of nuclear receptors, including FXR,LXR and/or orphan nuclear receptors, using the compounds andcompositions provided herein are also provided. The compounds andcompositions provided herein are active in assays that measure theactivity of nuclear receptors, including FXR, LXR and/or orphan nuclearreceptors, including the assays provided herein. These methods includeinhibiting and up-regulating the activity of nuclear receptors,including FXR, LXR and/or orphan nuclear receptors.

Methods of reducing cholesterol levels in a subject in need thereof byadministration of one or more compounds or compositions provided hereinare also provided.

Methods of modulating cholesterol metabolism using the compounds andcompositions provided herein are provided.

Methods of treating, preventing, or ameliorating one or more symptoms ofdiseases or disorders which are affected by cholesterol, triglyceride,or bile acid levels by administration of one or more of the compoundsand compositions provided herein are also provided.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds, which are formulated for systemic delivery, includingparenteral, oral, or intravenous delivery, or for local or topicalapplication, for the treatment of nuclear receptor, including FXR, LXRand/or orphan nuclear receptor, mediated diseases or disorders, ordiseases or disorders in which nuclear receptor activity, including FXR,LXR and/or orphan nuclear receptor activity, is implicated, including,but not limited to, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus,dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris,acneiform skin conditions, diabetes, Parkinson's disease, cancer,Alzheimer's disease, inflammation, immunological disorders, lipiddisorders, obesity, conditions characterized by a perturbed epidermalbarrier function, hyperlipidemia, cholestasis, peripheral occlusivedisease, ischemic stroke, conditions of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane, orcardiovascular disorders, are administered to an individual exhibitingthe symptoms of these diseases or disorders. The amounts are effectiveto ameliorate or eliminate one or more symptoms of the diseases ordisorders.

Articles of manufacture containing packaging material, a compound orcomposition, or pharmaceutically acceptable derivative thereof, providedherein, which is effective for modulating the activity of nuclearreceptors, including FXR, LXR and/or orphan nuclear receptors, or fortreatment, prevention or amelioration of one or more symptoms of nuclearreceptor, including FXR, LXR and/or orphan nuclear receptor, mediateddiseases or disorders, or diseases or disorders in which nuclearreceptor activity, including FXR, LXR and/or orphan nuclear receptoractivity, is implicated, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable derivative thereof, is used for modulating the activity ofnuclear receptors, including FXR, LXR and/or orphan nuclear receptors,or for treatment, prevention or amelioration of one or more symptoms ofnuclear receptor, including FXR, LXR and/or orphan nuclear receptor,mediated diseases or disorders, or diseases or disorders in whichnuclear receptor activity, including FXR, LXR and/or orphan nuclearreceptor activity, is implicated, are provided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 provides in vitro data for the compounds whose synthesis isdescribed in the Examples. Average EC₅₀ (“EC50_AVG”) for FXR agonism isprovided as follows: A=0.0001–0.01 μM, B=0.01–0.1 μM, C=0.1–1.0 μM,D=1.0–10.0 μM and NC=not calculated or inactive. Average percentefficacy (“EFF_AVG”) for FXR agonism relative to control(chenodeoxycholic acid, CDCA) is provided as follows: A=>150%,B=100–150%, C=50–100%, D=0–50% and NC=not calculated or inactive.Average IC₅₀ (“IC50_AVG”) for FXR antagonism is provided as follows:A=0.0001–0.01 μM, B=0.01–0.1 μM, C=0.1–1.0 μM and D=1.0–10.0 μM. Averagepercent inhibition (“INHIB_AVG”) for FXR antagonism relative to control(chenodeoxycholic acid, CDCA) is provided as follows: E=>75%, F=50–75%,G=25–50%, H=0–25% and NEG=negative.

DETAILED DESCRIPTION OF EMBODIMENTS

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

As used herein, a nuclear receptor is a member of a superfamily ofregulatory proteins that are receptors for, e.g., steroids, retinoids,vitamin D and thyroid hormones. These proteins bind to cis-actingelements in the promoters of their target genes and modulate geneexpression in response to a ligand therefor. Nuclear receptors may beclassified based on their DNA binding properties. For example, theglucocorticoid, estrogen, androgen, progestin and mineralocorticoidreceptors bind as homodimers to hormone response elements (HREs)organized as inverted repeats. Another example are receptors, includingthose activated by retinoic acid, thyroid hormone, vitamin D₃, fattyacids/peroxisome proliferators and ecdysone, that bind to HREs asheterodimers with a common partner, the retinoid X receptor (RXR). Amongthe latter receptors are FXR and LXR.

As used herein, an orphan nuclear receptor is a nuclear receptor forwhich the natural ligand is unknown.

As used herein, the term farnesoid X receptor or FXR refers to allmammalian forms of such receptor including, for example, alternativesplice isoforms and naturally occurring isoforms. Representative FXRspecies include, without limitation rat FXR (SEQ ID NO. 5), mouse FXR,and human FXR (SEQ ID NO. 7).

As used herein, liver X receptor or LXR or UR refers to a nuclearreceptor implicated in cholesterol homeostasis. As used herein, the termLXR refers to both LXRα and LXRβ, two forms of the protein found inmammals. Liver X receptor-α or LXRα refers to the receptor described inU.S. Pat. No. 5,757,661 and Willy et a. (1995) Gene Dev. 9(9):1033–1045.Liver X receptor-β or LXRβ refers to the receptor described in Peet etal. (1998) Curr. Opin. Genet. Dev. 8(5):571–575; Song et al. (1995) Ann.N.Y. Acad. Sci. 761:38–49; Alberti et al. (2000) Gene 243(1–2):93–103;and references cited therein.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydratesor prodrugs thereof. Such derivatives may be readily prepared by thoseof skill in this art using known methods for such derivatization. Thecompounds produced may be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl andheterocyclyl esters of acidic groups, including, but not limited to,carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids,sulfinic acids and boronic acids. Pharmaceutically acceptable enolethers include, but are not limited to, derivatives of formula C═C(OR)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl ar heterocyclyl. Pharmaceutically acceptableenol esters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating a nuclear receptor,including FXR, LXR and/or orphan nuclear receptor, mediated diseases ordisorders, or diseases or disorders in which nuclear receptor activity,including FXR, LXR and/or orphan nuclear receptor activity, isimplicated.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of FXR activity, in an assay that measuressuch response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized by one or more steps or processes orotherwise converted to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, thepharmaceutically active compound is modified such that the activecompound will be regenerated by metabolic processes. The prodrug may bedesigned to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound (see,e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages 388–392).

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. In the case of amino acid residues, suchresidues may be of either the L- or D-form. The configuration fornaturally occurring amino acid residues is generally L. When notspecified the residue is the L form. As used herein, the term “aminoacid” refers to α-amino acids which are racemic, or of either the D- orL-configuration. The designation “d” preceding an amino acid designation(e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid.The designation “dl” preceding an amino acid designation (e.g., dlPip)refers to a mixture of the L- and D-isomers of the amino acid. It is tobe understood that the chiral centers of the compounds provided hereinmay undergo epimerization in vivo. As such, one of skill in the art willrecognize that administration of a compound in its (R) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound. The instant disclosure is meant to include all such possibleisomers, as well as, their racemic and optically pure forms. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as reverse phase HPLC. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is usedas is generally understood by those of skill in this art.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, or 1 to 16 carbons, and arestraight or branched. Alkenyl carbon chains of from 2 to 20 carbons, incertain embodiments, contain 1 to 8 double bonds, and the alkenyl carbonchains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 doublebonds. Alkynyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.Exemplary alkyl, alkenyl and alkynyl groups herein include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-penytyl and isohexyl.As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer tocarbon chains having from about 1 or about 2 carbons up to about 6carbons. As used herein, “alk(en)(yn)yl” refers to an alkyl groupcontaining at least one double bond and at least one triple bond.

As used herein, “cycloalkyl” refers to a saturated mono- or multicyclicring system, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl referto mono- or multicyclic ring systems that respectively include at leastone double bond and at least one triple bond. Cycloalkenyl andcycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbonatoms, with cycloalkenyl groups, in further embodiments, containing 4 to7 carbon atoms and cycloalkynyl groups, in further embodiments,containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl,cycloalkenyl and cycloalkynyl groups may be composed of one ring or twoor more rings which may be joined together in a fused, bridged orspiro-connected fashion. “Cycloalk(en)(yn)yl” refers to a cycloalkylgroup containing at least one double bond and at least one triple bond.

As used herein, “substituted alkyl,” “substituted alkenyl,” “substitutedalkynyl,” “substituted cycloalkyl,” “substituted cycloalkenyl,” and“substitued cycloalkynyl” refer to alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and cycloalkynyl groups, respectively, that are substitutedwith one or more substituents, in certain embodiments one to three orfour substituents, where the substituents are as defined herein,generally selected from Q¹.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 6 to 19 carbon atoms. Aryl groups include, butare not limited to groups such as fluorenyl, substituted fluorenyl,phenyl, substituted phenyl, naphthyl and substituted naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrrolidinyl,pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl,quinolinyl and isoquinolinyl.

As used herein, a “heteroarylium” group is a heteroaryl group that ispositively charged on one or more of the heteroatoms.

As used herein, “heterocyclyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiment of 5 to 6members, where one or more, in certain embodiments, 1 to 3, of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur. Inembodiments where the heteroatom(s) is(are) nitrogen, the nitrogen isoptionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternizedto form an ammonium group where the substituents are selected as above.

As used herein, “substituted aryl,” “substituted heteroaryl” and“substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclylgroups, respectively, that are substituted with one or moresubstituents, in certain embodiments one to three or four substituents,where the substituents are as defined herein, generally selected fromQ¹.

As used herein, “aralkyl” refers to an alkyl group in which one of thehydrogen atoms of the alkyl is replaced by an aryl group.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups thatbehave substantially similar to halides. Such compounds can be used inthe same manner and treated in the same manner as halides. Pseudohalidesinclude, but are not limited to, cyanide, cyanate, thiocyanate,selenocyanate, trifluoromethoxy, and azide.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl, trifluoromethyl and1-chloro-2-fluoroethyl.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “sulfinyl” or “thionyl” refers to —S(O)—. As usedherein, “sulfonyl” or “sulfuryl” refers to —S(O)₂—. As used herein,“sulfo” refers to —S(O)₂O—.

As used herein, “carboxy” refers to a divalent radical, —C(O)O—.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R isalkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl”refers to —C(O)NR′R in which R′ and R are independently alkyl, includinglower alkyl; “carboxamide” refers to groups of formula —NR′COR in whichR′ and R are independently alkyl, including lower alkyl.

As used herein, “diarylaminocarbonyl” refers to —C(O)NRR′ in which R andR′ are independently selected from aryl, including lower aryl, such asphenyl.

As used herein, “arylalkylaminocarbonyl” refers to —C(O)NRR′ in whichone of R and R′ is aryl, including lower aryl, such as phenyl, and theother of R and R′ is alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which R isaryl, including lower aryl, such as phenyl.

As used herein, “hydroxycarbonyl” refers to —COOH.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,including lower alkyl.

As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R is aryl,including lower aryl, such as phenyl.

As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, in whichR is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, in whichR is aryl, including lower aryl, such as phenyl.

As used herein, “alkylene” refers to a straight, branched or cyclic, incertain embodiments straight or branched, divalent aliphatic hydrocarbongroup, in one embodiment having from 1 to about 20 carbon atoms, inanother embodiment having from 1 to 12 carbons. In a further embodimentalkylene includes lower alkylene. There may be optionally inserted alongthe alkylene group one or more oxygen, sulfur, including S(═O) andS(═O)₂ groups, or substituted or unsubstituted nitrogen atoms, including—NR— and —N⁺RR— groups, where the nitrogen substituent(s) is(are) alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl or COR′, where R′ is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, —OY or —NYY, where Y ishydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylenegroups include, but are not limited to, methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—(CH₂)₃—), methylenedioxy (—O—CH₂—O—) andethylenedioxy (—O—(CH₂)₂—O—). The term “lower alkylene” refers toalkylene groups having 1 to 6 carbons. In certain embodiments, alkylenegroups are lower alkylene, including alkylene of 1 to 3 carbon atoms.

As used herein, “azaalkylene” refers to —(CRR)_(n)—NR—(CRR)_(m)—, wheren and m are each independently an integer from 0 to 4. As used herein,“oxaalkylene” refers to —(CRR)_(n)—O—(CRR)_(m)—, where n and m are eachindependently an integer from 0 to 4. As used herein, “thiaalkylene”refers to —(CRR)_(n)—S—(CRR)_(m)—, —(CRR)_(n)—S(═O)—(CRR)_(m)—, and—(CRR)_(n)—S(═O)₂—(CRR)_(m)—, where n and m are each independently aninteger from 0 to 4. In certain embodiments herein, the “R” groups inthe definitions of azaalkylene, oxaalkylene and thiaalkylene are eachindependently selected from hydrogen and Q¹, as defined herein.

As used herein, “alkenylene” refers to a straight, branched or cyclic,in one embodiment straight or branched, divalent aliphatic hydrocarbongroup, in certain embodiments having from 2 to about 20 carbon atoms andat least one double bond, in other embodiments 1 to 12 carbons. Infurther embodiments, alkenylene groups include lower alkenylene. Theremay be optionally inserted along the alkenylene group one or moreoxygen, sulfur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl. Alkenylene groups include, but are notlimited to, —CH═CH—CH═CH— and —CH═CH—CH₂—. The term “lower alkenylene”refers to alkenylene groups having 2 to 6 carbons. In certainembodiments, alkenylene groups are lower alkenylene, includingalkenylene of 3 to 4 carbon atoms.

As used herein, “alkynylene” refers to a straight, branched or cyclic,in certain embodiments straight or branched, divalent aliphatichydrocarbon group, in one embodiment having from 2 to about 20 carbonatoms and at least one triple bond, in another embodiment 1 to 12carbons. In a further embodiment, alkynylene includes lower alkynylene.There may be optionally inserted along the alkynylene group one or moreoxygen, sulfur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl. Alkynylene groups include, but are notlimited to, —C≡C—C≡C—, —C≡C— and —C≡C—CH₂—. The term “lower alkynylene”refers to alkynylene groups having 2 to 6 carbons. In certainembodiments, alkynylene groups are lower alkynylene, includingalkynylene of 3 to 4 carbon atoms.

As used herein, “alk(en)(yn)ylene” refers to a straight, branched orcyclic, in certain embodiments straight or branched, divalent aliphatichydrocarbon group, in one embodiment having from 2 to about 20 carbonatoms and at least one triple bond, and at least one double bond; inanother embodiment 1 to 12 carbons. In further embodiments,alk(en)(yn)ylene includes lower alk(en)(yn)ylene. There may beoptionally inserted along the alkynylene group one or more oxygen,sulfur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl. Alk(en)(yn)ylene groups include, but arenot limited to, —C═C—(CH₂)_(n)—C≡C—, where n is 1 or 2. The term “loweralk(en)(yn)ylene” refers to alk(en)(yn)ylene groups having up to 6carbons. In certain embodiments, alk(en)(yn)ylene groups have about 4carbon atoms.

As used herein, “cycloalkylene” refers to a divalent saturated mono- ormulticyclic ring system, in certain embodiments of 3 to 10 carbon atoms,in other embodiments 3 to 6 carbon atoms; cycloalkenylene andcycloalkynylene refer to divalent mono- or multicyclic ring systems thatrespectively include at least one double bond and at least one triplebond. Cycloalkenylene and cycloalkynylene groups may, in certainembodiments, contain 3 to 10 carbon atoms, with cycloalkenylene groupsin certain embodiments containing 4 to 7 carbon atoms andcycloalkynylene groups in certain embodiments containing 8 to 10 carbonatoms. The ring systems of the cycloalkylene, cycloalkenylene andcycloalkynylene groups may be composed of one ring or two or more ringswhich may be joined together in a fused, bridged or spiro-connectedfashion. “Cycloalk(en)(yn)ylene” refers to a cycloalkylene groupcontaining at least one double bond and at least one triple bond.

As used herein, “substituted alkylene,” “substituted alkenylene,”“substituted alkynylene,” “substituted cycloalkylene,” “substitutedcycloalkenylene,” and “substitued cycloalkynylene” refer to alkylene,alkenylene, alkynylene, cycloalkylene, cycloalkenylene andcycloalkynylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three or foursubstituents, where the substituents are as defined herein, generallyselected from Q¹.

As used herein, “arylene” refers to a monocyclic or polycyclic, incertain embodiments monocyclic, divalent aromatic group, in oneembodiment having from 5 to about 20 carbon atoms and at least onearomatic ring, in another embodiment 5 to 12 carbons. In furtherembodiments, arylene includes lower arylene. Arylene groups include, butare not limited to, 1,2-, 1,3- and 1,4-phenylene. The term “lowerarylene” refers to arylene groups having 5 or 6 carbons.

As used herein, “heteroarylene” refers to a divalent monocyclic ormulticyclic aromatic ring system, in one embodiment of about 5 to about15 members where one or more, in certain embodiments 1 to 3, of theatoms in the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur.

As used herein, “heterocyclylene” refers to a divalent monocyclic ormulticyclic non-aromatic ring system, in certain embodiments of 3 to 10members, in one embodiment 4 to 7 members, in another embodiment 5 to 6members, where one or more, including 1 to 3, of the atoms in the ringsystem is a heteroatom, that is, an element other than carbon, includingbut not limited to, nitrogen, oxygen or sulfur.

As used herein, “substituted arylene,” “substituted heteroarylene” and“substituted heterocyclylene” refer to arylene, heteroarylene andheterocyclylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three of foursubstituents, where the substituents are as defined herein, generallyselected from Q¹.

As used herein, “alkylidene” refers to a divalent group, such as ═CR′R″,which is attached to one atom of another group, forming a double bond.Alkylidene groups include, but are not limited to, methylidene (═CH₂)and ethylidene (═CHCH₃). As used herein, “arylalkylidene” refers to analkylidene group in which either R′ or R″ is an aryl group.“Cycloalkylidene” groups are those where R′ and R″ are linked to form acarbocyclic ring. “Heterocyclylidene” groups are those where at leastone of R′ and R″ contain a heteroatom in the chain, and R′ and R″ arelinked to form a heterocyclic ring.

As used herein, “amido” refers to the divalent group —C(O)NH—.“Thioamido” refers to the divalent group —C(S)NH—. “Oxyamido” refers tothe divalent group —OC(O)NH—. “Thiaamido” refers to the divalent group—SC(O)NH—. “Dithiaamido” refers to the divalent group —SC(S)NH—.“Ureido” refers to the divalent group —HNC(O)NH—. “Thioureido” refers tothe divalent group —HNC(S)NH—.

As used herein, “semicarbazide” refers to —NHC(O)NHNH—. “Carbazate”refers to the divalent group —OC(O)NHNH—. “Isothiocarbazate” refers tothe divalent group —SC(O)NHNH—. “Thiocarbazate” refers to the divalentgroup —OC(S)NHNH—. “Sulfonylhydrazide” refers to the group —SO₂NHNH—.“Hydrazide” refers to the divalent group —C(O)NHNH—. “Azo” refers to thedivalent group —N═N—. “Hydrazinyl” refers to the divalent group —NH—NH—.

Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there may be one or more substituents present. Forexample, “haloalkyl” may include one or more of the same or differenthalogens. As another example, “C₁₋₃alkoxyphenyl” may include one or moreof the same or different alkoxy groups containing one, two or threecarbons.

As used herein, the following terms have their accepted meaning in thechemical literature:

AcOH acetic acid CHCl₃ chloroform conc concentrated DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxideEtOAc ethyl acetate EtOH ethanol (100%) Et₂O diethyl ether Hex hexanesH₂SO₄ sulfuric acid MeCN acetonitrile MeOH methanol Pd/C palladium onactivated carbon TEA triethylamine THF tetrahydrofuran TFAtrifluoroacetic acid

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942–944).

B. Heterocyclic Modulators of Nuclear Receptors

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating farnesoid X receptor(FXR), liver X receptors (LXRα and LXRβ) and/or orphan nuclearreceptors, are provided.

In certain embodiments, the compounds are thiazolidinones, i.e.,compounds of formulae I where X² is S and X³ is O, that are substitutedwith a heterocyclylene group and an imine moiety. Thus, in theseembodiments, the compounds have formulae II:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

-   -   (i) A and G are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted cycloalkylalkyl,        substituted or unsubstituted heterocyclylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroaralkyl, substituted or unsubstituted        heteroarylium, substituted or unsubstituted heteroaryliumalkyl,        halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and        C(=J)R¹³, or A and G together form substituted or unsubstituted        alkylene, substituted or unsubstituted azaalkylene, substituted        or unsubstituted oxaalkylene, substituted or unsubstituted        thiaalkylene, substituted or unsubstituted alkenylene,        substituted or unsubstituted alkynylene, substituted or        unsubstituted 1,3-butadienylene, substituted or unsubstituted        1-aza-1,3-butadienylene, or substituted or unsubstituted        2-aza-1,3-butadienylene;        -   D and E are each independently selected from hydrogen,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted heterocyclyl, substituted or unsubstituted            cycloalkylalkyl, substituted or unsubstituted            heterocyclylalkyl, substituted or unsubstituted aryl,            substituted or unsubstituted heteroaryl, substituted or            unsubstituted aralkyl, substituted or unsubstituted            heteroaralkyl, halo and pseudohalo or D and E together form            a bond; or    -   (ii) A and D; or E and G; together form substituted or        unsubstituted alkylene, substituted or unsubstituted        azaalkylene, substituted or unsubstituted oxaalkylene, or        substituted or unsubstituted thiaalkylene;    -   and the others of A, D, E and G are selected as in (i);

X¹ is selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; R¹and R² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where:

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(=J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(=J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R¹, R², R³,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted orsubstituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene;

each Q¹ is independently unsubstituted or substituted with one or moresubstituents each independently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene;

each Q2 group is independently unsubstituted or substituted with one ormore, in one embodiment one, two or three, substituents eachindependently selected from alkyl, halo and pseudohalo;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In another embodiment, the compounds have formulae II:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

-   -   (i) A and G are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted cycloalkylalkyl,        substituted or unsubstituted heterocyclylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroaralkyl, substituted or unsubstituted        heteroarylium, substituted or unsubstituted heteroaryliumalkyl,        halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and        C(=J)R¹³, or A and G together form substituted or unsubstituted        alkylene, substituted or unsubstituted azaalkylene, substituted        or unsubstituted oxaalkylene, substituted or unsubstituted        thiaalkylene, substituted or unsubstituted alkenylene,        substituted or unsubstituted alkynylene, substituted or        unsubstituted 1,3-butadienylene, substituted or unsubstituted        1-aza-1,3-butadienylene, or substituted or unsubstituted        2-aza-1,3-butadienylene;        -   D and E are each independently selected from hydrogen,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted heterocyclyl, substituted or unsubstituted            cycloalkylalkyl, substituted or unsubstituted            heterocyclylalkyl, substituted or unsubstituted aryl,            substituted or unsubstituted heteroaryl, substituted or            unsubstituted aralkyl, substituted or unsubstituted            heteroaralkyl, halo and pseudohalo or D and E together form            a bond; or    -   (ii) A and D; or E and G; together form substituted or        unsubstituted alkylene, substituted or unsubstituted        azaalkylene, substituted or unsubstituted oxaalkylene, or        substituted or unsubstituted thiaalkylene;    -   and the others of A, D, E and G are selected as in (i);

X¹ is selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; R¹and R² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where:

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(=J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(=J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R¹, R², R³,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted orsubstituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q¹ groups, which substitute the same atom, together formalkylene;

each Q¹ is independently unsubstituted or substituted with one or moresubstituents each independently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In another embodiment, A and G are each independently selected fromhydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, or together form substituted or unsubstituted1,3-butadienyl. In a further embodiment, A and G are each independentlyhydrogen, substituted or unsubstituted methyl, substituted orunsubstituted naphthyl, or substituted or unsubstituted phenyl, ortogether form 1,3-butadienyl. In another embodiment, A and G are bothhydrogen.

In another embodiment, D and E are each hydrogen, or together form abond.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae I where D and E together form abond, and A and G together form 1,3-butadienyl. Thus, in thisembodiment, the compounds have formulae III:

or a pharmaceutically acceptable derivative thereof, where R¹, R², R³,X¹, X² and X³ are selected as above; each R⁴ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, substituted orunsubstituted guanidino, substituted or unsubstituted isothioureido,halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(=J)R¹³;x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkylmoieties of R⁴ are unsubstituted or substituted with one or moresubstituents each independently selected from Q², as defined above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae IV:

or a pharmaceutically acceptable derivative thereof, where R¹, R², R³,X¹, X² and X³ are selected as above; each R⁴ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, substituted orunsubstituted guanidino, substituted or unsubstituted isothioureido,halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(=J)R¹³;x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkylmoieties of R⁴ are unsubstituted or substituted with one or more, incertain embodiments one to three or four, substituents eachindependently selected from Q², as defined above.

In certain embodiments herein, the compounds are of formulae III or IV,and are selected with the proviso that when R³ is substituted orunsubstituted heteroarylium then the heteroatom substituent is not alkylor aryl. In another embodiment, the compounds are of formulae III or IV,and are selected with the proviso that R³ is not substituted orunsubstituted heteroarylium or substituted or unsubstitutedheteroaryliumalkyl. In other embodiments, the compounds are of formulaIII or IV and are selected with the proviso that R³ is not heteroaryl.In further embodiments, the compounds are of formula III or IV and areselected with the proviso that R³ is not alkyl. In another embodiment,the compounds are of formula III or IV and are selected with the provisothat R³ is not heterocycloaryl (i.e., an aryl groups possessing a fusedheterocyclic moiety).

In certain embodiments herein, X¹ is O, S or NR⁵. In other embodiments,X¹ is O or S. In another embodiment, X¹ is S.

In other embodiments, R¹ is substituted or unsubstituted alkyl. Infurther embodiments, R¹ is methyl.

In another embodiment, R² is substituted or unsubstituted alkyl orsubstituted or unsubstituted aralkyl. In further embodiments, R² isethyl, n-butyl or benzyl. In another embodiment, R² is benzyl. Inanother embodiment, R² is substituted or unsubstituted heteroaralkyl. Inanother embodiment, R² is pyridylmethyl. In another embodiment, R² ispicolyl (i.e., 2-, 3-, or 4-pyridylmethyl). In another embodiment, R² is2-furylmethyl. In another embodiment, R² is 3-pyridylmethyl.

In another embodiment, R³ is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl. In further embodiments, R³ issubstituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl, substituted or unsubstituted pyridyl, substituted orunsubstituted indazolyl, or substituted or unsubstituted quinolinyl. Inanother embodiment, R³ is substituted or unsubstituted quinolyl,substituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl, substituted or unsubstituted isoquinolyl, substituted orunsubstituted pyridyl, or substituted or unsubstituted indazolyl. Incertain embodiments, R³ is substituted or unsubstituted phenyl orsubstituted or unsubstituted naphthyl. In another embodiment, R³ issubstituted or unsubstituted phenyl.

In another embodiment, Q¹ is selected from halo, hydroxy, nitrile,nitro, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, heteroaryl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy,aralkoxy, hydroxyimino, alkoxyimino, aralkoxyimino, arylazo,haloalkylcarbonylamino, amino, alkylamino, dialkylamino, haloalkylamino,alkylcarbonylamino, dialkylcarbonyloxy or heterocyclyl; or two Q¹groups, which substitute atoms in a 1,2 arrangement, form alkylenedioxy.In another embodiment, Q¹ is selected from halo, hydroxy, nitrile,nitro, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, heteroaryl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy,aralkoxy, amino, alkylamino, dialkylamino, haloalkylamino,alkylcarbonylamino, dialkylcarbonyloxy or heterocyclyl; or two Q¹groups, which substitute atoms in a 1,2 arrangement, form alkylenedioxy.In further embodiments, Q¹ is methoxy, dimethylamino, NH₂, benzyloxy,hydroxy, CN, isopropyl, methyl, nitro, ethylamino, trifluoromethyl,acetyl, chloro, n-propyl, ethoxy, methylcarbonylamino, CONH₂,methoxycarbonyl, methylamino, trifluoromethoxy, imidazolyl,hydroxycarbonyl, isopropylamino, tert-butylamino,2,2,2-trifluoroethylamino, piperidinyl, dimethylaminocarbonyloxy,2-hydroxyethoxy, 2-(N-morpholinyl)ethoxy or morpholinyl, or two Q¹groups, which substitute atoms in a 1,2 arrangement, formmethylenedioxy. In another embodiment, Q¹ is hydroxycarbonyl orethylamino.

In further embodiments, the compounds for use in the compositions andmethods provided herein are of formulae IV where x is 0, R¹ is methyl,R² is benzyl, X¹ is S and R³ is a substituted or unsubstituted phenylgroup. Thus, in these embodiments, the compounds have formulae V:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo,pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido,ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring,together form alkylenedioxy; and

the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ areunsubstituted or substituted with one or more substituents, in oneembodiment one to three or four substituents, each independentlyselected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxyor alkylenedioxy.

In another embodiment, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independentlyselected from hydrogen, halo, hydroxy, nitrile, nitro, hydroxycarbonyl,alkyl, haloalkyl, polyhaloalkyl, heteroaryl, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy, aralkoxy, amino,alkylamino, dialkylamino, haloalkylamino, alkylcarbonylamino orheterocyclyl; or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substituteadjacent carbons on the ring, form alkylenedioxy. In furtherembodiments, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently hydrogen,methoxy, dimethylamino, NH₂, benzyloxy, hydroxy, CN, isopropyl, methyl,nitro, ethylamino, trifluoromethyl, acetyl, chloro, n-propyl, ethoxy,methylcarbonylamino, CONH₂, methoxycarbonyl, methylamino,trifluoromethoxy, imidazolyl, hydroxycarbonyl, isopropylamino,tert-butylamino, 2,2,2-trifluoroethylamino, piperidinyl or morpholinyl,or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacentcarbons on the ring, form methylenedioxy.

In another embodiment, A is phenyl which is unsubstituted or issubstituted with one or more, in one embodiment, one, two or three,groups each independently selected from Q¹.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; A is phenyl; G is hydrogen; and D and E together form a bond.Thus, in this embodiment, the compounds have formulae VI:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; A and G are hydrogen; and D and E together form a bond. Thus,in this embodiment, the compounds have formulae VII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; and A, G, D and E are hydrogen. Thus, in this embodiment, thecompounds have formulae VIII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; A is phenyl; G is methyl; and D and E together form a bond.Thus, in this embodiment, the compounds have formulae IX:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds provided herein have formulae V–XI,where R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from(i) or (ii) as follows:

(i) R²¹ is ethylamino; R¹⁸ is cyano; and R¹⁷, R¹⁹ and R²⁰ are eachhydrogen; or

(ii) R¹⁷ is ethylamino; R²⁰ is cyano; and R¹⁸, R¹⁹ and R²¹ are eachhydrogen.

In certain embodiments, the compounds have formulae I, where X¹, X² andX³ are selected from (i) or (ii) as follows: (i) X¹, X² and X³ are eachindependently S, O or NR⁵; or (ii) X¹ is —CR⁸═CR⁹—, where R⁸ and R⁹ areas defined herein, and X² and X³ are each independently S, O or NR⁵; R¹is substituted or unsubstituted alkyl, where there are 0 to 6substituents selected from alkoxy, alkoxyalkyl, hydroxycarbonyl,alkylcarbonyloxy, hydroxy, halo, pseudohalo, aryl and heteroaryl; R² issubstituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heteroaralkyl, or substituted or unsubstitutedheterocyclylalkyl; where there are 0 or 1 substituents selected fromalkoxycarbonyl and hydroxycarbonyl; R³ is substituted or unsubstitutedheteroaryl, substituted or unsubstituted aryl, or substituted orunsubstituted aralkyl; where there are 0 to 5 substituents selected fromalkylamino, cyano, cycloalkyl, hydroxy, alkoxy, dialkylamino, amino,heterocyclyl, aralkoxy, alkyl, nitro, haloalkyl, alkylcarbonyl, halo,alkylcarbonylamino, alkoxyalkylcarbonylamino,dialkylaminoalkylcarbonylamino, aminocarbonyl, alkoxycarbonyl,aralkylamino, cycloalkylamino, heterocyclylamino, haloalkylamino,haloalkoxy, hydroxycarbonyl, aminosulfonyl, alkylcarbonylaminosulfonyl,or haloalkylcarbonylamino, or any two substituents, which substituteatoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy; A and Gare each independently selected from hydrogen, substituted orunsubstituted aryl, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxycarbonyl, hydroxycarbonyl, and substituted orunsubstituted alkylcarbonyl, where there are 0 to 5 substituentsselected from aryl, haloalkyl, haloalkoxy, nitro, halo, pseudohalo,hydroxy, alkyl and alkoxy, or A and G together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene orsubstituted or unsubstituted 1,3-butadienylene, in one embodimentsubstituted or unsubstituted alkylene, where there are 0 to 4substituents selected from halo, pseudohalo, alkoxy, nitro, haloalkyl,alkylcarbonylamino, hydroxy, alkylaminocarbonyloxy,alkoxycarbonylalkoxy, aminocarbonylalkoxy, hydroxyalkoxy, alkyl,haloalkylaminocarbonyloxy and alkylaminoalkoxy; D and E are eachhydrogen, or together form a bond; and R⁵ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹⁴R¹⁵ or C(=J)R¹³; R¹⁰ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(=J)R¹³; J is O, S or NR¹⁴; R¹³ isselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted cycloalkylalkyl, substitutedor unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected fromhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl andheteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl and heteroaralkyl moieties of R⁵, R¹⁰ and R¹³ are unsubstitutedor substituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aralkoxyimino, arylazo,haloalkylcarbonylamino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In certain embodiments, the compounds have formulae I, where X¹, X² andX³ are each independently S, O or NR⁵; R¹ is substituted orunsubstituted alkyl, where there are 0 to 6 substituents selected fromhalo, pseudohalo, aryl and heteroaryl; R² is substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heteroaralkyl,or substituted or unsubstituted heterocyclylalkyl; where there are 0 or1 substituents selected from alkoxycarbonyl and hydroxycarbonyl; R³ issubstituted or unsubstituted heteroaryl, substituted or unsubstitutedaryl, or substituted or unsubstituted aralkyl; where there are 0 to 5substituents selected from alkylamino, cyano, cycloalkyl, hydroxy,alkoxy, dialkylamino, amino, heterocyclyl, aralkoxy, alkyl, nitro,haloalkyl, alkylcarbonyl, halo, alkylcarbonylamino, aminocarbonyl,alkoxycarbonyl, aralkylamino, cycloalkylamino, heterocyclylamino,haloalkylamino, haloalkoxy, hydroxycarbonyl, aminosulfonyl,alkylcarbonylaminosulfonyl, or haloalkylcarbonylamino, or any twosubstituents, which substitute atoms in a 1,2 or 1,3 arrangement,together form alkylenedioxy; A and G are each independently selectedfrom hydrogen, substituted or unsubstituted aryl, substituted orunsubstituted alkyl and substituted or unsubstituted alkylcarbonyl,where there are 0 to 5 substituents selected from nitro, halo,pseudohalo, alkyl and alkoxy, or A and G together form substituted orunsubstituted alkylene or substituted or unsubstituted1,3-butadienylene, in one embodiment substituted or unsubstitutedalkylene, where there are 0 to 4 substituents selected from halo,pseudohalo, alkoxy, nitro, haloalkyl, alkylcarbonylamino, hydroxy,alkylaminocarbonyloxy, alkoxycarbonylalkoxy, aminocarbonylalkoxy,hydroxyalkoxy, alkyl, haloalkylaminocarbonyloxy and alkylaminoalkoxy; Dand E are each hydrogen, or together form a bond; and R⁵ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹⁴R¹⁵ or C(=J)R¹³; R¹⁰ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O,S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl moieties of R⁵, R¹⁰ and R¹³are unsubstituted or substituted with one or more substituents eachindependently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy,oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—) or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is1 or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In certain embodiments, the compounds claimed herein exhibit improved invitro activity, efficacy, potency and/or pharmacokinetic properties,such as solubility, oral half-life, bioavailability, oral absorption,and/or in vivo activity, over related commercially available compoundsor related compounds disclosed previously.

In certain embodiments, A and G are selected with the proviso that A andG are not both methyl. In another embodiment, A and G together formbutadienyl with the proviso that the resulting benzo-fused group is notsubstituted at the 5-position with methoxy or chloro and is notsubstituted at the 6-position with methoxy or methyl. In anotherembodiment, A and G together form butadienyl with the proviso that theresulting benzo-fused group is not substituted at the 5-position withalkoxy or halo and is not substituted at the 6-position with alkoxy oralkyl. In another embodiment, A and G together form butadienyl with theproviso that the resulting benzo-fused group is not substituted withmethoxy, methyl or chloro. In another embodiment, A and G together formbutadienyl with the proviso that the resulting benzo-fused group is notsubstituted with alkoxy, alkyl or halo.

In another embodiment, X¹ is S. In another embodiment, X¹ is —CR⁸═CR⁹—.In another embodiment, X² is S. In another embodiment, X³ is O.

In another embodiment, R¹ is substituted alkyl. In another embodiment,R¹ is 2-methoxy-1-ethyl, 3-methoxy-1-propyl, methoxycarbonylmethyl,hydroxycarbonylmethyl, 2-acetoxy-1-ethyl or 2-hydroxy-1-ethyl. Inanother embodiment, R¹ is unsubstituted alkyl. In other embodiments, R¹is methyl.

In another embodiment, R² is benzyl, phenyl, allyl, ethyl, butyl,cyclohexyl, propyl, 3-pyridylmethyl, 2-furylmethyl,4-methoxycarbonylbenzyl, 4-hydroxycarbonylbenzyl, 2-phenethyl or2-(4-morpholinyl)ethyl. In another embodiment, R² is benzyl. In anotherembodiment, R² is pyridylmethyl. In another embodiment, R² is picolyl(i.e., 2-, 3-, or 4-pyridylmethyl). In another embodiment, R² is2-furylmethyl. In another embodiment, R² is 3-pyridylmethyl.

In another embodiment, R³ is substituted or unsubstituted quinolyl,substituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl, substituted or unsubstituted isoquinolyl, substituted orunsubstituted pyridyl, or substituted or unsubstituted indazolyl. Inanother embodiment, R³ is substituted or unsubstituted phenyl. In otherembodiments, R³ is substituted with 0 to 5 substituents selected fromethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino,4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl,isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl,ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl,methoxymethylcarbonylamino, dimethylaminomethylcarbonylamino,butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino,pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl,trifluoromethoxy, hydroxycarbonyl, aminosulfonyl,methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino andt-butoxycarbonyl, or any two substituents, which substitute atoms in a1,2 arrangement, together form methylenedioxy. In further embodiments,R³ is 5-quinolyl, 2-ethylamino-5-cyanophenyl, 4-cyclohexylphenyl,2-hydroxy-1-naphthyl, 6-quinolyl, 3-methoxyphenyl,4-dimethylaminophenyl, 4-aminophenyl, 4-(4-morpholinyl)phenyl,2-methylamino-5-cyanophenyl, 2-dimethylamino-5-cyanophenyl,2-ethylaminophenyl, 3-cyanophenyl, 2-aminophenyl,2-isopropylamino-5-cyanophenyl, 4-benzyloxyphenyl,2-methyl-4-hydroxy-5-isopropylphenyl, 2-ethylamino-5-nitrophenyl,3-trifluoromethylphenyl, 3-methylcarbonylphenyl, 3-chlorophenyl,2-propylphenyl, 2-ethoxyphenyl, 3-methylcarbonylaminophenyl,3-aminocarbonylphenyl, 3-methoxycarbonylphenyl, 8-quinolyl,8-hydroxy-5-quinolyl, 2-butylamino-5-cyanophenyl,2-benzylamino-5-cyanophenyl, 2-cyclopentylamino-5-cyanophenyl,2-(1-pyrrolidinyl)amino-5-cyanophenyl, 5-isoquinolyl, 1-isoquinolyl,4-methylcarbonylaminophenyl, 2-t-butylamino-5-cyanophenyl,2-(2,2,2-trifluoroethyl)amino-5-cyanophenyl,2-piperidinyl-5-cyanophenyl, 4-methylcarbonylphenyl,4-aminocarbonylphenyl, 2-ethylamino-5-methoxymethylcarbonylaminophenyl,2-ethylamino-5-dimethylaminomethylcarbonylaminophenyl, 1-naphthyl,2-naphthyl, 2-pyridyl, 3-pyridyl, 2-ethoxy-5-methylcarbonylaminophenyl,4-pyridyl, 4-methoxycarbonylphenyl, 4-trifluoromethoxyphenyl,5-indazolyl, 4-(imidazol-1-yl)phenyl, 3,4-methylenedioxyphenyl,3-hydroxycarbonylphenyl, 2-ethylamino-5-methylcarbonylphenyl,4-aminosulfonylphenyl, 4-methylcarbonylaminosulfonylphenyl,3-methylcarbonylphenyl, 2-methylcarbonylamino-5-pyridyl,4-cyano-3-methylcarbonylaminophenyl,2-methylamino-5-methylcarbonylphenyl,4-trifluoromethylcarbonylaminophenyl,2-ethylamino-5-methoxycarbonylphenyl, 2-hydroxycarbonylphenyl or2-ethylamino-5-t-butoxycarbonylphenyl.

In another embodiment, A and G are each independently selected fromhydrogen, substituted or unsubstituted phenyl, substituted orunsubstituted methyl, substituted or unsubstituted naphthyl,hydroxycarbonyl, substituted and unsubstituted ethoxycarbonyl, andsubstituted or unsubstituted methylcarbonyl, or A and G together fromsubstituted or unsubstituted butylene, substituted or unsubstitutedpropylene, substituted or unsubstituted methyleneazaethylene, orsubstituted or unsubstituted 1,3-butadienylene. In other embodiments, Aand G are each independently selected from hydrogen, substituted orunsubstituted phenyl, substituted or unsubstituted methyl, substitutedor unsubstituted naphthyl, and substituted or unsubstitutedmethylcarbonyl, and are substituted with 0 to 4 substituents selectedfrom chloro, bromo, methoxy, fluoro, ethoxy, nitro,trifluoromethylcarbonylamino, dimethylaminocarbonyloxy,2-(1-piperidinyl)ethoxy, 2-(1-methyl-4-piperazinyl)ethoxy,2-(N-morpholinyl)ethoxy, 2-dimethylaminoethoxy, hydroxycarbonylmethoxy,methylcarbonylamino, phenyl, trifluoromethyl, trifluoromethoxy, hydroxy,ethylaminocarbonyloxy, methoxycarbonylmethoxy, aminocarbonylmethoxy,2-hydroxyethoxy, 2-hydroxypropoxy, methyl, 2-chloroethylaminocarbonyloxyand 2-methylaminoethoxy. In further embodiments, A and G together formsubstituted or unsubstituted 1,3-butadienylene and are substituted with0 to 5 substituents selected from nitro, fluoro, chloro, methyl andmethoxy. In another embodiment, A and G are each independently selectedfrom hydrogen, 4-phenylphenyl, 4-trifluoromethylphenyl,2-trifluoromethylphrnyl, 4-trifluoromethoxyphenyl, 4-nitrophenyl,4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, methyl,2-naphthyl, 4-bromophenyl, 2-methoxyphenyl, 3-fluorophenyl,2,4-dimethoxyphenyl, ethoxycarbonyl, benzyl, hydroxycarbonyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl andmethylcarbonyl, or A and G together form 1,3-butadienylene,2-chloro-1,3-butadienylene, 2-methoxy-1,3-butadienylene,2-fluoro-1,3-butadienylene, 2-ethoxy-1,3-butadienylene,2-nitro-1,3-butadienylene, 2-trifluoromethyl-1,3-butadienylene,2-trifluoromethoxy-1,3-butadienylene,2-methylcarbonylamino-1,3-butadienylene,2-trifluoromethylcarbonylamino-1,3-butadienylene,2-aminocarbonylmethoxy-1,3-butadienylene,2-(2-hydroxyethoxy)-1,3-butadienylene,2-(3-hydroxypropoxy)-1,3-butadienylene,2-dimethylaminocarbonyloxy-1,3-butadienylene,2-(1-piperidinyl)ethoxy-1,3-butadienylene,2-(4-(1-methylpiperazin)yl)ethoxy-1,3-butadienylene,2-(4-morpholinyl)ethoxy-1,3-butadienylene,2-dimethylaminoethoxy-1,3-butadienylene,2-hydroxycarbonylmethoxy-1,3-butadienylene, 2-hydroxy-1,3-butadienylene,2-ethylaminocarbonyloxy-1,3-butadienylene,2-methoxycarbonylmethoxy-1,3-butadienylene,2-aminocarbonylmethoxy-1,3-butadienylene,2-(2-hydroxyethoxy)-1,3-butadienylene, 1-methoxy-1,3-butadienylene,1-methyl-1,3-butadienylene, 1-chloro-1,3-butadienylene,2-(2-chloroethylaminocarbonyloxy)-1,3-butadienylene or2-(2-methylaminoethoxy)-1,3-butadienylene.

In another embodiment, D and E are each hydrogen or together form abond.

In certain embodiments herein, the compounds are selected from thefollowing compounds. In other embodiments, the compounds are selectedfrom those disclosed in the Examples. All isomers of these compounds arewithin the scope of the disclosure herein:

-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-phenylimino-thiazolidine-4-one;-   3-benzyl-2-(4-methoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-2-(4-dimethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   2-(4-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)thiazolidine-4-one;-   2-(2-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-2-(4-benzyloxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-2-(2-hydroxy-1-naphthylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;-   3-benzyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-2-(2-ethylamino-5-nitrophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[3-(trifluoromethyl)phenylimino]thiazolidine-4-one;-   2-(3-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-2-(3-chlorophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-propylphenylimino)thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidine-4-one;-   3-benzyl-2-(2-ethoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic    acid, methyl ester;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-3-ylimino)thiazolidine-4-one;-   N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethoxyphenyl}acetamide;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-4-ylimino)thiazolidine-4-one;-   4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic    acid, methyl ester;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[4-(trifluoromethoxy)phenylimino]thiazolidine-4-one;-   3-benzyl-2-(1H-indazol-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one;-   3-benzyl-2-(4-imidazol-1-ylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   2-(benzo[1,3]dioxol-5-ylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic    acid;-   3-benzyl-2-[2-(ethylamino)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(dimethylamino)benzonitrile;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(tert-butylamino)benzonitrile;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2,2,2-trifluoroethylamino)benzonitrile;-   3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-piperidin-1-ylbenzonitrile;-   2-[5-acetyl-2-(ethylamino)phenylimino]-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one;-   3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)thiazolidin-4-one;-   3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-morpholin-4-yl-phenylimino)thiazolidin-4-one;-   3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile;-   4-dimethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;-   3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile;-   3-[3-butyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;-   3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one;-   N-[4-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)phenyl]acetamide;-   2′-[5-acetyl-2-(ethylamino)phenylimino]-3′-benzyl-3-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one;-   3-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazol-yliden-2′-ylideneamino)-4-(ethylamino)benzonitrile;-   N-[4-(3′-benzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)phenyl]acetamide;-   N-[4-(3′-benzyl-3-methyl-4′-oxo-[2,5′]bithiazolidinyliden-2′-ylideneamino)phenyl]acetamide;-   3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-5-chloro-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyclohexylphenyl)imino-thiazolidine-4-one;-   3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one;-   4-ethylamino-3-[3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-5-methoxy-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-quinolyl)imino-thiazolidine-4-one;-   4-ethylamino-3-[3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-benzylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-quinolyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-hydroxy-5-quinolyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-isoquinolyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-isoquinolyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylamino)phenylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonyl)phenylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminocarbonyl)phenylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-naphthyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-naphthyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-pyridyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminosulfonyl)phenylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylaminosulfonyl)phenylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-methylcarbonyl)phenylimino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylcarbonylamino-5-pyridyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyano-5-methylcarbonylaminophenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-trifluoromethylcarbonylaminophenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methoxycarbonylphenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxycarbonylphenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-tert-butoxycarbonylphenyl)imino-thiazolidine-4-one;-   4-butylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-cyclopentylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-pyrrolidinylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-pyrrolidinyl-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-hydroxy-2-methyl-5-isopropylphenyl)imino-thiazolidine-4-one;-   3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one;-   4-ethylamino-3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(6-nitro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-trifluoromethyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(6-methylcarbonylamino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-ethylaminocarbonyloxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-methoxycarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-aminocarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(4-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(4-methyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(4-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-(2-chloroethylaminocarbonyloxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(5-(2-methylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-propyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-acetylphenyl)imino-thiazolidine-4-one;-   3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;-   4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-(2-furylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-(4-methoxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;-   3-(4-hydroxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;-   4-ethylamino-3-[3-(2-phenylethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-(2-(4-morpholinyl)-1-ethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   3-benzyl-5-(3-methylthiazolin-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;-   3-benzyl-5-(3-methylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-dimethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenyl-5-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-ethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-nitrophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-fluorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-chlorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methylphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methoxyphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methyl-5-acetylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-propylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-diphenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;-   4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;    and-   3-(4-methoxycarbonylbenzyl)-5-(3-methyl-4,5-butylenyllthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one.

In certain embodiments herein, the compounds provided herein are FXR orLXR antagonists. In these embodiments, the compounds have formulae I,where A and G are each independently substituted or unsubstitutedphenyl, substituted or unsubstituted naphthyl, or substituted orunsubstituted methyl, substituted or unsubstituted ethyl or togetherform substituted or unsubstituted butadienylene where there are 0 to 4substituents, in one embodiment 0 or 1 substituents, selected frommethylcarbonylamino, hydroxy, trifluoromethoxy, trifluorocarbonylamino,aminocarbonylmethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,dimethylaminocarbonyloxy, 2-(1-piperidinyl)ethoxy,2-(4-(1-methylpiperazin)yl)ethoxy, 2-(4-morpholinyl)ethoxy,2-dimethylaminoethoxy and hydroxycarbonylmethoxy; D and E form a bond;X¹ and X² are both S; X³ is O; R¹ is methyl; R² is benzyl; and R³ is5-cyano-2-ethylaminophenyl.

In certain embodiments, FXR or LXR antagonists provided herein areselected from the following compounds. All isomer of these compounds arewithin the scope of the disclosure herein:

-   3-(3′-Benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylamino-benzonitrile;-   3-(3′-Benzyl-5-ethyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylamino-benzonitrile;-   3-(3′-Benzyl-3-methyl-4-naphthalen-2-yl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylamino-benzonitrile;-   3-[3′-Benzyl-4-(4-bromophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;-   3-[3′-Benzyl-4-(2-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;-   3-[3′-Benzyl-4-(3-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;-   3-[3′-Benzyl-4-(2,4-dimethoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;-   N-{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxo-thiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-acetamide;-   3-[3-Benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]-4-ethylamino-benzonitrile;-   3-[3-Benzyl-5-(3-methyl-6-trifluoromethoxy-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]-4-ethylamino-benzonitrile;-   N-{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxo-thiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-2,2,2-trifluoroacetamide;-   2-{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}-acetamide;-   3-{3-Benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;-   3-{3-Benzyl-5-[5-(3-hydroxypropoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;-   Dimethylcarbamic acid    2-[3-benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl    ester;-   3-{3-Benzyl-5-[3-methyl-5-(2-piperidin-1-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;-   3-(3-Benzyl-5-{3-methyl-5-[2-(4-methylpiperazin-1-yl)-ethoxy]-3H-benzothiazol-2-ylidene}-4-oxothiazolidin-2-ylideneamino)-4-ethylamino-benzonitrile;-   3-{3-Benzyl-5-[3-methyl-5-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;-   3-{3-Benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;    and-   {2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}-acetic    acid.

In another embodiment, the compounds for use in the compositions andmethods provided herein are shown in the Examples. All isomers of thesecompounds are within the scope of this disclosure.

C. Preparation of the Compounds

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures. Allcommercially available compounds were used without further purificationunless otherwise indicated. CDCl₃ (99.8% D, Cambridge IsotopeLaboratories) was used in all experiments as indicated. Proton (¹H)nuclear magnetic resonance (NMR) spectra were recorded on a BrukerAvance 400 MHz NMR spectrometer. Significant peaks are tabulated andtypically include: number of protons, and multiplicity (s, singlet; d,double; t, triplet; q, quartet; m, multiplet; br s, broad singlet).Chemical shifts are reported as parts per million (δ) relative totetramethylsilane. Low-resolution mass spectra (MS) were obtained aselectrospray ionization (ESI) mass spectra, which were recorded on aPerkin-Elmer SCIEX HPLC/MS instrument using reverse-phase conditions(acetonitrile/water, 0.05% trifluoroacetic acid). Flash chromatographywas performed using Merck Silica Gel 60 (230–400 mesh) followingstandard protocol (Still et al. (1978) J. Org. Chem. 43, 2923).

The following illustrations depict general preparations of compoundsclaimed herein and consist of reactions typically known to one skilledin the art of chemical synthesis. The substituents A, D, E, G, R¹–R³ andX¹—X³ have been previously described. Also it will be apparent to oneskilled in the art that many of the products could exist as one or moreisomers, that is E/Z isomers, enantiomers and/or diastereomers.

As shown above, treatment of 2-(alkylthio)azole (1) with an alkylatingagent (R¹X) affords the corresponding 2-(alkylthio)azolium complex (2),which then is condensed with 2-iminoazolidine (3) in the presence of abase to yield heterocycle (4). Thus, for example, when 1 is a1,3-heterocycle such as thiazole (X¹=S; E and D form a bond) that isalkylated with methyl p-toluenesulfonate, an intermediate N-methylthiazolium complex 2 is prepared (see, e.g., U.S. Pat. Nos. 5,707,794and 2,388,963). Subsequently, for example, when 3 is an2-iminothiazolidinone (X²=S and X³=O), an2-imino-5-(thiazol-2-ylidene)thiazolidin-4-one 4 is generated. Likewise,other heterocycles 1, such as but not limited to thiazoles, thiazolines,benzimidazoles, benzoxazoles, quinolines, pyridines and indoles, shouldundergo this transformation when bearing a 2-alkylthio or 2-mercaptosubstituent.

The synthesis of intermediate 2 is alternatively prepared from thecorresponding thione precursor (5) upon alkylation with RX. For example,when 5 is thiazolin-2-thione (X¹=S) that is alkylated with methylp-toluenesulfonate (RX), an intermediate N-alkyl2-(thiomethyl)thiazolinium complex 2 is generated.

Furthermore, for example, when the thione precursor 5 isthiazole-2-thione (X¹=S; E and D form a bond), it can be prepared by thecondensation of a dithiocarbamate salt (X¹=S) with a α-haloketone, asdepicted below (see, e.g., Bellec et al. (1999) Chem. Mater. 11:3147;Humphlett et al. (1964) J. Org. Chem. 29:2146). Various dithiocarbamatesalts are synthesized, for example, by reacting a primary amine, e.g.,methylamine, with carbon disulfide in the presence of a base such asEt₃N (see, e.g., Humphlett et al. (1964) J. Org. Chem. 29:2146). Thethiazole-2-thione 5 can then be transformed into the correspondingthiazolium complex 2.

Alternatively, as depicted below, reaction of intermediate 2 withazolidin-2-thione (6) in the presence of base gives anotherazolidin-2-thione (7). Treatment of intermediate 7 with an alkylatingagent (RX) affords the 2-(alkylthio)azolium complex (8), which reactswith an amine in the presence of base to yield heterocycle 4. Thus, forexample, when 6 is a 1,3-heterocycle such as rhodanine (X²=S and X³=O)that is condensed with an intermediate N-methyl benzothiazolium complex2 (X¹=S; E and D form a bond; A and G form a fused benzene), a5-(benzothiazol-2-ylidene)thiazolidin-4-one-2-thione 7 is generated(see, e.g., U.S. Pat. Nos. 5,618,831 and 2,454,629). Subsequentlyintermediate 7 is alkylated with, for example, methyl p-toluenesulfonateto give a 5-(benzothiazol-2-ylidene)-2-methylthio-4-oxothiazolidiniumcomplex 8, which can react with, for example, an aniline to yield an2-imino-5-(benzothiazol-2-ylidene)thiazolidin-4-one 4 (see, e.g., U.S.Pat. No. 5,618,831).

In general, 2-iminoazolidines 3 may be prepared as depicted below. Thus,for example, when 3 is an 2-imino-4-thiazolidinone (X²=S and X³=O), itcan be prepared by condensing a thiourea (X²=S) with a 2-haloester(X³═O) in the presence of base, in which R³ is typically aryl orheteroaryl (see, e.g., Seada et al. (1993) Indian J. Heterocycl. Chem.3:81; and International Patent Application Publication No. WO 00/42031).

Likewise 2-iminoazolidines 3 may be prepared from a carbodiimide asdepicted below. For example, when 3 is an 2-imino-4-imidazolidinone(X²═NR and X³=O), it can be prepared by reacting a carbodiimide with a2-aminoester (X²=NR and X³=O). Also an 2-imino-4-oxazolidinones (X² andX³=O) can be prepared from a carbodiimide and a 2-hydroxyester.

Similarly azolidine-2-thiones 6 may be prepared as depicted below. Thus,for example, when 6 is a rhodanine (X²=S and X³=O), it can be preparedby condensing an isothiocyanate with a 2-mercaptoester (see, e.g., Doganet al. (1992) Tetrahedron 48:7157; and Drobnica et al. (1972) Chem.Zvesti 26:538). Also imidazolidin-4-one-2-thiones (X²=NR and X³=O) oroxazolidin-4-one-2-thiones (X² and X³=O) can be prepared by reacting anisothiocyanate with 2-aminoester or 2-hydroxyester, respectively.

Alkyl and aryl isothiocyanates, aryl amines, rhodanines, unsymmetricalcarbodiimides and thioureas may be synthesized utilizing knownmethodology (see, e.g., Katritzky et al. (1984) ComprehensiveHeterocyclic Chemistry; Pergamon Press: Oxford, UK; Katritzky et al.(2000) Handbook of Heterocyclic Chemistry, 2^(nd) Ed.; Pergamon Press:Oxford, UK; March Advanced Organic Chemistry, 4^(th) Ed.; John Wiley:New York (1992); and International Patent Application Publication No. WO00/42031). For example, alkyl and aryl isothiocyanates are readilyprepared from reaction of an amine with thiophosgene or a thiophosgeneequivalent, e.g. thiocarbonyl diimidazole. Many isothiocyanates also arecommercially available. Unsymmetrical thioureas are prepared fromreaction of an isothiocyanate with an amine.

D. Formulation of Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of the nuclear receptor activitymodulators provided herein that are useful in the prevention, treatment,or amelioration of one or more of the symptoms of diseases or disordersassociated with nuclear receptor activity, including FXR, LXR and/ororphan nuclear receptor activity. Such diseases or disorders include,but are not limited to, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus,dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris,acneiform skin conditions, diabetes, Parkinson's disease, cancer,Alzheimer's disease, inflammation, immunological disorders, lipiddisorders, obesity, conditions characterized by a perturbed epidermalbarrier function, hyperlipidemia, cholestasis, peripheral occlusivedisease, ischemic stroke, conditions of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane, andcardiovascular disorders.

The compositions contain one or more compounds provided herein. Thecompounds are preferably formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as transdermal patch preparationand dry powder inhalers. Typically the compounds described above areformulated into pharmaceutical compositions using techniques andprocedures well known in the art (see, e.g., Ansel Introduction toPharmaceutical Dosage Forms, Fourth Edition 1985, 126).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives is (are) mixed with asuitable pharmaceutical carrier or vehicle. The compounds may bederivatized as the corresponding salts, esters, enol ethers or esters,acids, bases, solvates, hydrates or prodrugs prior to formulation, asdescribed above. The concentrations of the compounds in the compositionsare effective for delivery of an amount, upon administration, thattreats, prevents, or ameliorates one or more of the symptoms of diseasesor disorders associated with nuclear receptor activity or in whichnuclear receptor activity is implicated. Such diseases or disordersinclude, but are not limited to, hypercholesterolemia,hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy,hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis,gallstone disease, acne vulgaris, acneiform skin conditions, diabetes,Parkinson's disease, cancer, Alzheimer's disease, inflammation,immunological disorders, lipid disorders, obesity, conditionscharacterized by a perturbed epidermal barrier function, hyperlipidemia,cholestasis, peripheral occlusive disease, ischemic stroke, conditionsof disturbed differentiation or excess proliferation of the epidermis ormucous membrane, and cardiovascular disorders.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) maybe formed by drying down egg phosphatidyl choline and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of acompound provided herein in phosphate buffered saline lacking divalentcations (PBS) is added and the flask shaken until the lipid film isdispersed. The resulting vesicles are washed to remove unencapsulatedcompound, pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand in International Patent Application Publication Nos. 99/27365 and00/25134 (see, e.g., EXAMPLES 53 and 54) and then extrapolated therefromfor dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofdiseases or disorders associated with nuclear receptor activity or inwhich nuclear receptor activity is implicated, as described herein.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50–100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.001 mg to about 2000 mg of compound per kilogramof body weight per day. Pharmaceutical dosage unit forms are prepared toprovide from about 1 mg to about 1000 mg and preferably from about 10 toabout 500 mg of the essential active ingredient or a combination ofessential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingdiseases or disorders associated with nuclear receptor activity or inwhich nuclear receptor activity is implicated, as described herein. Theconcentration of active compound in the composition will depend onabsorption, inactivation, excretion rates of the active compound, thedosage schedule, amount administered, particular formulation as well asother factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including orally, parenterally, rectally, topically and locally. Fororal administration, capsules and tablets are presently preferred. Thecompositions are in liquid, semi-liquid or solid form and are formulatedin a manner suitable for each route of administration. Preferred modesof administration include parenteral and oral modes of administration.Oral administration is presently most preferred.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol or other syntheticsolvent; antimicrobial agents, such as benzyl alcohol and methylparabens; antioxidants, such as ascorbic acid and sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid (EDTA);buffers, such as acetates, citrates and phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. Parenteralpreparations can be enclosed in ampules, disposable syringes or singleor multiple dose vials made of glass, plastic or other suitablematerial.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.Derivatives of the compounds, such as prodrugs of the compounds may alsobe used in formulating effective pharmaceutical compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are typically formulated andadministered in unit-dosage forms or multiple-dosage forms. Unit-doseforms as used herein refers to physically discrete units suitable forhuman and animal subjects and packaged individually as is known in theart. Each unit-dose contains a predetermined quantity of thetherapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes and individually packaged tablets or capsules.Unit-dose forms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

The composition can contain along with the active ingredient: a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethylcellulose; a lubricant, such as magnesium stearate, calciumstearate and talc; and a binder such as starch, natural gums, such asgum acaciagelatin, glucose, molasses, polyinylpyrrolidine, cellulosesand derivatives thereof, povidone, crospovidones and other such bindersknown to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrine derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound in an amount sufficient to alleviate the symptoms of thetreated subject.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain 0.001%–100% activeingredient, preferably 0.1–85%, typically 75–95%.

The active compounds or pharmaceutically acceptable derivatives may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings. The compositions may include other active compounds to obtaindesired combinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, mayalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as diseases ordisorders associated with nuclear receptor activity or in which nuclearreceptor activity is implicated. It is to be understood that suchcombination therapy constitutes a further aspect of the compositions andmethods of treatment provided herein.

1. Compositions for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms,preferably capsules or tablets. The tablets, pills, capsules, trochesand the like can contain any of the following ingredients, or compoundsof a similar nature: a binder; a diluent; a disintegrating agent; alubricant; a glidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow-release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, acompound provided herein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylenevinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (10–1000 mg,preferably 100–500 mg) or multiple dosages of the compound. Thelyophilized powder can be stored under appropriate conditions, such asat about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1–50 mg, preferably 5–35 mg, more preferably about9–30 mg of lyophilized powder, is added per mL of sterile water or othersuitable carrier. The precise amount depends upon the selected compound.Such amount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will typically have diameters ofless than 50 microns, preferably less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%–10% isotonic solutions, pH about 5–7, withappropriate salts.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Articles of Manufacture

The compounds or pharmaceutically acceptable derivatives may be packagedas articles of manufacture containing packaging material, a compound orpharmaceutically acceptable derivative thereof provided herein, which iseffective for modulating the activity of nuclear receptors, includingFXR, LXR and/or orphan nuclear receptors, or for treatment, preventionor amelioration of one or more symptoms of nuclear receptor, includingFXR, LXR and/or orphan nuclear receptor, mediated diseases or disorders,or diseases or disorders in which nuclear receptor activity, includingFXR, LXR and/or orphan nuclear receptor activity, is implicated, withinthe packaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable derivative thereof, is usedfor modulating the activity of nuclear receptors, including FXR, LXRand/or orphan nuclear receptors, or for treatment, prevention oramelioration of one or more symptoms of nuclear receptor, including FXR,LXR and/or orphan nuclear receptor, mediated diseases or disorders, ordiseases or disorders in which nuclear receptor activity, including FXR,LXR and/or orphan nuclear receptor activity, is implicated.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease or disorder in which nuclearreceptor activity, including FXR, LXR and/or orphan nuclear receptoractivity, is implicated as a mediator or contributor to the symptoms orcause.

E. Evaluation of the Activity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that modulate the activity or nuclear receptors,including the FXR. Such assays include, for example, biochemical assayssuch as binding assays, fluorescence polarization assays, FRET basedcoactivator recruitment assays (see generally Glickman et al., J.Biomolecular Screening, 7 No. 1 3–10 (2002)), as well as cell basedassays including the co-transfection assay, the use of LBD-Gal 4chimeras and protein-protein interaction assays (see, Lehmann. et al.,J. Biol Chem., 272(6) 3137–3140 (1997).

High throughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments Inc., Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass.) that enable these assays to be run in a high throughputmode. These systems typically automate entire procedures, including allsample and reagent pipetting, liquid dispensing timed incubations, andfinal readings of the microplate in detector(s) appropriate for theassay. These configurable systems provide high throughput and rapidstart up as well as a high degree of flexibility and customization. Themanufacturers of such systems provide detailed protocols for varioushigh throughput systems. Thus, for example, Zymark Corp. providestechnical bulletins describing screening systems for detecting themodulation of gene transcription, ligand binding, and the like.

Assays that do not require washing or liquid separation steps arepreferred for such high throughput screening systems and includebiochemical assays such as fluorescence polarization assays (see forexample, Owicki, J., Biomol Screen 2000 October;5(5):297) scintillationproximity assays (SPA) (see for example, Carpenter et al., Methods MolBiol 2002;190:31–49) and fluorescence resonance energy transfer energytransfer (FRET) or time resolved FRET based coactivator recruitmentassays (Mukherjee et al., J Steroid Biochem Mol Biol 2002July;81(3):217–25; (Zhou et al., Mol Endocrinol. 1998October;12(10):1594–604). Generally such assays can be preformed usingeither the full length receptor, or isolated ligand binding domain(LBD). In the case of FXR, the LBD comprises amino acids 244 to 472 ofthe full length sequence.

If a fluorescently labeled ligand is available, fluorescencepolarization assays provide a way of detecting binding of compounds tothe nuclear receptor of interest by measuring changes in fluorescencepolarization that occur as a result of the displacement of a traceamount of the label ligand by the compound. Additionally this approachcan also be used to monitor the ligand dependent association of afluorescently labeled coactivator peptide to the nuclear receptor ofinterest to detect ligand binding to the nuclear receptor of interest.

The ability of a compound to bind to a receptor, or heterodimer complexwith RXR, can also be measured in a homogeneous assay format byassessing the degree to which the compound can compete off aradiolabelled ligand with known affinity for the receptor using ascintillation proximity assay (SPA). In this approach, the radioactivityemitted by a radiolabelled compound generates an optical signal when itis brought into close proximity to a scintillant such as a Ysi-coppercontaining bead, to which the nuclear receptor is bound. If theradiolabelled compound is displaced from the nuclear receptor the amountof light emitted from the nuclear receptor bound scintillant decreases,and this can be readily detected using standard microplate liquidscintillation plate readers such as, for example, a Wallac MicroBetareader.

The heterodimerization of FXR with RXRα can also be measured byfluorescence resonance energy transfer (FRET), or time resolved FRET, tomonitor the ability of the compounds provided herein to bind to FXR orother nuclear receptors. Both approaches rely upon the fact that energytransfer from a donor molecule to an acceptor molecule only occurs whendonor and acceptor are in close proximity. Typically the purified LBD ofthe nuclear receptor of interest is labeled with biotin then mixed withstoichiometric amounts of europium labeled streptavidin (Wallac Inc.),and the purified LBD of RXRα is labeled with a suitable fluorophore suchas CY5™. Equimolar amounts of each modified LBD are mixed together andallowed to equilibrate for at least 1 hour prior to addition to eithervariable or constant concentrations of the sample for which the affinityis to be determined. After equilibration, the time-resolved fluorescentsignal is quantitated using a fluorescent plate reader. The affinity ofthe compound can then be estimated from a plot of fluorescence versusconcentration of compound added.

This approach can also be exploited to measure the ligand dependentinteraction of a co-activator peptide with a nuclear receptor in orderto characterize the agonist or antagonist activity of the compoundsdisclosed herein. Typically the assay in this case involves the use arecombinant Glutathione-S-transferase (GST)-nuclear receptor ligandbinding domain (LBD) fusion protein and a synthetic biotinylated peptidesequenced derived from the receptor interacting domain of a co-activatorpeptide such as the steroid receptor coactivator 1 (SRC-1). TypicallyGST-LBD is labeled with a europium chelate (donor) via a europium-taggedanti-GST antibody, and the coactivator peptide is labeled withallophycocyanin via a streptavidin-biotin linkage.

In the presence of an agonist for the nuclear receptor, the peptide isrecruited to the GST-LBD bringing europium and allophycocyanin intoclose proximity to enable energy transfer from the europium chelate tothe allophycocyanin. Upon excitation of the complex with light at 340 nmexcitation energy absorbed by the europium chelate is transmitted to theallophycocyanin moiety resulting in emission at 665 nm. If the europiumchelate is not brought in to close proximity to the allophycocyaninmoiety there is little or no energy transfer and excitation of theeuropium chelate results in emission at 615 nm. Thus the intensity oflight emitted at 665 nm gives an indication of the strength of theprotein-protein interaction. The activity of a nuclear receptorantagonist can be measured by determining the ability of a compound tocompetitively inhibit (i.e., IC₅₀) the activity of an agonist for thenuclear receptor.

In addition a variety of cell based assay methodologies may besuccessfully used in screening assays to identify and profile thespecificity of compounds of the present invention. These approachesinclude the co-transfection assay, translocation assays, complementationassays and the use of gene activation technologies to over expressendogenous nuclear receptors.

Three basic variants of the co-transfection assay strategy exist,co-transfection assays using full-length nuclear receptor, cotransfection assays using chimeric nuclear receptors comprising theligand binding domain of the nuclear receptor of interest fused to aheterologous DNA binding domain, and assays based around the use of themammalian two hybrid assay system.

The basic co-transfection assay is based on the co-transfection into thecell of an expression plasmid to express the nuclear receptor ofinterest in the cell with a reporter plasmid comprising a reporter genewhose expression is under the control of DNA sequence that is capable ofinteracting with that nuclear receptor (See for example U.S. Pat. Nos.5,071,773; 5,298,429 and 6,416,957). Treatment of the transfected cellswith an agonist for the nuclear receptor increases the transcriptionalactivity of that receptor which is reflected by an increase inexpression of the reporter gene, which may be measured by a variety ofstandard procedures.

For those receptors that function as heterodimers with RXR, such as FXR,the co-transfection assay typically includes the use of expressionplasmids for both the nuclear receptor of interest and RXR. Typicalco-transfection assays require access to the full length nuclearreceptor and suitable response elements that provide sufficientscreening sensitivity and specificity to the nuclear receptor ofinterest.

Genes encoding the following full-length previously described proteins,which are suitable for use in the co-transfection studies and profilingthe compounds described herein, include rat FXR (SEQ ID NO. 5), humanFXR (SEQ ID NO.7), human RXR α (SEQ ID NO. 9), human RXR β (SEQ ID NO.17), human RXR γ (SEQ ID NO. 15), human LXR α (SEQ ID NO. 1), human LXRβ (SEQ ID NO. 3), human PPARα (SEQ ID NO. 11) and human PPAR δ (SEQ IDNO. 13).

Reporter plasmids may be constructed using standard molecular biologicaltechniques by placing cDNA encoding for the reporter gene downstreamfrom a suitable minimal promoter. For example luciferase reporterplasmids may be constructed by placing cDNA encoding firefly luciferaseimmediately down stream from the herpes virus thymidine kinase promoter(located at nucleotides residues −105 to +51 of the thymidine kinasenucleotide sequence) which is linked in turn to the various responseelements.

Numerous methods of co-transfecting the expression and reporter plasmidsare known to those of skill in the art and may be used for theco-transfection assay to introduce the plasmids into a suitable celltype. Typically such a cell will not endogenously express nuclearreceptors that interact with the response elements used in the reporterplasmid.

Numerous reporter gene systems are known in the art and include, forexample, alkaline phosphatase Berger, J., et al. (1988) Gene 66 1–10;Kain, S. R. (1997) Methods. Mol. Biol. 63 49–60), β-galactosidase (See,U.S. Pat. No. 5,070,012, issued Dec, 3, 1991 to Nolan et al., andBronstein, I., et al., (1989) J. Chemilum. Biolum. 4 99–111),chloramphenicol acetyltransferase (See Gorman et al., Mol Cell Biol.(1982) 2 1044–51), β-glucuronidase, peroxidase, β-lactamase (U.S. Pat.Nos. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (U.S.Pat. Nos. 5,221,623; 5,683,888; 5,674,713; 5,650,289; 5,843,746) andnaturally fluorescent proteins (Tsien, R. Y. (1998) Annu. Rev. Biochem.67 509–44).

The use of chimeras comprising the ligand binding domain (LBD) of thenuclear receptor of interest to a heterologous DNA binding domain (DBD)expands the versatility of cell based assays by directing activation ofthe nuclear receptor in question to defined DNA binding elementsrecognized by defined DNA binding domain (see WO95/18380). This assayexpands the utility of cell based co-transfection assays in cases wherethe biological response or screening window using the native DNA bindingdomain is not satisfactory.

In general the methodology is similar to that used with the basicco-transfection assay, except that a chimeric construct is used in placeof the full length nuclear receptor. As with the full length nuclearreceptor, treatment of the transfected cells with an agonist for thenuclear receptor LBD increases the transcriptional activity of theheterologous DNA binding domain which is reflected by an increase inexpression of the reporter gene as described above. Typically for suchchimeric constructs, the DNA binding domains from defined nuclearreceptors, or from yeast or bacterially derived transcriptionalregulators such as members of the GAL 4 and Lex A/Umud super familiesare used.

A third cell based assay of utility for screening compounds of thepresent invention is a mammalian two-hybrid assay that measures theability of the nuclear hormone receptor to interact with a cofactor inthe presence of a ligand. (See for example, U.S. Pat. Nos. 5,667,973,5,283,173 and 5,468,614). The basic approach is to create three plasmidconstructs that enable the interaction of the nuclear receptor with theinteracting protein to be coupled to a transcriptional readout within aliving cell. The first construct is an expression plasmid for expressinga fusion protein comprising the interacting protein, or a portion ofthat protein containing the interacting domain, fused to a GAL4 DNAbinding domain. The second expression plasmid comprises DNA encoding thenuclear receptor of interest fused to a strong transcription activationdomain such as VP16, and the third construct comprises the reporterplasmid comprising a reporter gene with a minimal promoter and GAL4upstream activating sequences.

Once all three plasmids are introduced into a cell, the GAL4 DNA bindingdomain encoded in the first construct allows for specific binding of thefusion protein to GAL4 sites upstream of a minimal promoter. Howeverbecause the GAL4 DNA binding domain typically has no strongtranscriptional activation properties in isolation, expression of thereporter gene occurs only at a low level. In the presence of a ligand,the nuclear receptor-VP16 fusion protein can bind to theGAL4-interacting protein fusion protein bringing the strongtranscriptional activator VP16 in close proximity to the GAL4 bindingsites and minimal promoter region of the reporter gene. This interactionsignificantly enhances the transcription of the reporter gene, which canbe measured for various reporter genes as described above. Transcriptionof the reporter gene is thus driven by the interaction of theinteracting protein and nuclear receptor of interest in a liganddependent fashion.

Any compound which is a candidate for activation of FXR may be tested bythese methods. Generally, compounds are tested at several differentconcentrations to optimize the chances that activation of the receptorwill be detected and recognized if present. Typically assays areperformed in triplicate and vary within experimental error by less than15%. Each experiment is typically repeated three or more times withsimilar results.

Activity of the reporter gene can be conveniently normalized to theinternal control and the data plotted as fold activation relative tountreated cells. A positive control compound (agonist) may be includedalong with DMSO as high and low controls for normalization of the assaydata. Similarly, antagonist activity can be measured by determining theability of a compound to competitively inhibit the activity of anagonist.

Additionally the compounds and compositions can be evaluated for theirability to increase or decrease the expression of genes known to bemodulated by FXR and other nuclear receptors in vivo, usingNorthern-blot, RT PCR or oligonucleotide microarray analysis to analyzeRNA levels. Western-blot analysis can be used to measure expression ofproteins encoded by FXR target genes. Genes that are known to beregulated by the FXR include cholesterol 7 a-hydroxylase (CYP7A1), therate limiting enzyme in the conversion of cholesterol to bile acids, thesmall heterodimer partner-1 (SHP-1), the bile salt export pump (BSEP,ABCB11), canalicular bile acid export protein, sodium taurocholatecotransporting polypeptide (NTCP, SLC10A1) and intestinal bile acidbinding protein (I-BABP).

Established animal models exist for a number of diseases of directrelevance to the claimed compounds and these can be used to furtherprofile and characterize the claimed compounds. These model systemsinclude diabetic dislipidemia using Zucker (fa/fa) rats or (db/db) mice,spontaneous hyperlipidemia using apolipoprotein E deficient mice(ApoE^(−/−)), diet-induced hyperlipidemia, using low density lipoproteinreceptor deficient mice (LDR^(−/−)) and atherosclerosis using both theApo E(^(−/−)) and LDL(^(−/−)) mice fed a western diet. (21% fat, 0.05%cholesterol). Additionally FXR or LXR animal models (e.g., knockoutmice) can be used to further evaluate the present compounds andcompositions in vivo (see, for example, Sinal, et al., Cell, 102:731–744 (2000), Peet, et al., Cell, 93:693–704 (1998)).

F. Methods of Use of the Compounds and Compositions

Methods of use of the compounds and compositions provided herein arealso provided. The methods involve both in vitro and in vivo uses of thecompounds and compositions for altering nuclear receptor activity,including FXR, LXR and/or orphan nuclear receptor activity, and fortreatment, prevention, or amelioration of one or more symptoms ofdiseases or disorder that are modulated by nuclear receptor activity,including FXR, LXR and/or orphan nuclear receptor activity, or in whichnuclear receptor activity, including FXR, LXR and/or orphan nuclearreceptor activity, is implicated.

Methods of reducing cholesterol levels and of modulating cholesterolmetabolism are provided. As described above, FXR is implicated inmodulating cholesterol metabolism, catabolism and absorption of dietarycholesterol. See, e.g., International Patent Application Publication No.00/40965.

Method of altering nuclear receptor activity, including FXR, LXR and/ororphan nuclear receptor activity, by contacting the receptor with one ormore compounds or compositions provided herein, are provided.

Methods of treatment, prevention, or amelioration of one or moresymptoms of a disease or disorder which is affected by cholesterol,triglyceride, or bile acid levels are provided.

Methods of treatment, prevention, or amelioration of one or moresymptoms of hypercholesterolemia (see, e.g., International PatentApplication Publication No. WO 00/57915); hyperlipoproteinemia (see,e.g., International Patent Application Publication No. WO 01/60818);hypertriglyceridemia, lipodystrophy, hyperglycemia or diabetes mellitus(see, e.g., International Patent Application Publication No. WO01/82917); dyslipidemia, obesity, atherosclerosis, lipid disorders,cardiovascular disorders, or gallstone disease (see, e.g., InternationalPatent Application Publication No. WO 00/37077); acne vulgaris oracneiform skin conditions (see, e.g., International Patent ApplicationPublication No. WO 00/49992); atherosclerosis, diabetes, Parkinson'sdisease, inflammation, immunological disorders, obesity, cancer orAlzheimer's disease (see, e.g., International Patent ApplicationPublication No. WO 00/17334); conditions characterized by a perturbedepidermal barrier function, hyperlipidemia, cholestasis, peripheralocclusive disease, ischemic stroke, or conditions of disturbeddifferentiation or excess proliferation of the epidermis or mucousmembrane (see, e.g., U.S. Pat. Nos. 6,184,215 and 6,187,814, andInternational Patent Application Publication No. WO 98/32444) areprovided.

Methods of increasing cholesterol efflux from mammalian cells using thecompounds and compositions provided herein are provided (see, e.g.,International Patent Application Publication No. WO 00/78972).

Methods of increasing the expression of ATP-Binding Cassette (ABC1) inmammalian cells using the compounds and compositions provided herein areprovided (see, e.g., International Patent Application Publication No. WO00/78972).

Further provided herein are methods for the treatment, prevention, oramelioration of one or more symptoms of cholestasis, as well as treatingthe complications of cholestasis by administering a compound providedherein.

Cholestasis is typically caused by factors within the liver(intrahepatic) or outside the liver (extrahepatic) and leads to theaccumulation of bile salts, bile pigment bilirubin, and lipids in theblood stream instead of being eliminated normally.

Intrahepatic cholestasis is characterized by widespread blockage ofsmall ducts or by disorders, such as hepatitis, that impair the body'sability to eliminate bile. Intrahepatic cholestasis may also be causedby alcoholic liver disease, primary biliary cirrhosis, cancer that hasspread (metastasized) from another part of the body, primary sclerosingcholangitis, gallstones, biliary colic and acute cholecystitis. It canalso occur as a complication of surgery, serious injury, infection, orintravenous feeding or be drug induced. Cholestasis may also occur as acomplication of pregnancy and often develops during the second and thirdtrimesters.

Extrahepatic cholestasis is most often caused by choledocholithiasis(Bile Duct Stones), benign biliary strictures (non-cancerous narrowingof the common duct), cholangiocarcinoma (ductal carcinoma) andpancreatic carcinoma. Extrahepatic cholestasis can occur as a sideeffect of many medications.

Accordingly, compounds provided herein may be used for the treatment,prevention, or amelioration of one or more symptoms of intrahepatic orextrahepatic cholestasis, including without limitation, biliary artesia,obstetric cholestasis, neonatal cholestasis, drug induced cholestasis,cholestasis arising from Hepatitis C infection, chronic cholestaticliver disease such as primary biliary cirrhosis (PBC) and primarysclerosing cholangitis (PSC).

Methods of treating, preventing, or ameliorating one or more symptoms ofhypocholesterolemia using the compounds and compositions provided hereinare also provided.

G. Combination Therapy

Also contemplated herein is combination therapy using a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, incombination with one or more of the following: antihyperlipidemicagents, plasma HDL-raising agents, antihypercholesterolemic agents,cholesterol biosynthesis inhibitors (such as HMG CoA reductaseinhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and rivastatin), acyl-coenzyme A:cholesterol acytransferase(ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide,cholesterol absorption inhibitors, bile acid sequestrants (such as anionexchange resins, or quaternary amines (e.g., cholestyramine orcolestipol)), low density lipoprotein receptor inducers, clofibrate,fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B₆, vitaminB₁₂, anti-oxidant vitamins, β-blockers, anti-diabetes agents,angiotensin II antagonists, angiotensin converting enzyme inhibitors,platelet aggregation inhibitors, fibrinogen receptor antagonists,aspirin or fibric acid derivatives. The compound provided herein, orpharmaceutically acceptable derivative thereof, is administeredsimultaneously with, prior to, or after administration of one or more ofthe above agents. Pharmaceutical compositions containing a compoundprovided herein and one or more of the above agents are also provided.

Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a FXR selective compound and one ormore additional active agents, as well as administration of the FXRselective compound and each active agent in its own separatepharmaceutical dosage formulation. For example, a FXR agonist orantagonist of the present invention and an HMG-COA reductase inhibitorcan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, the compounds described herein and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

The compound is preferably administered with a cholesterol biosynthesisinhibitor, particularly an HMG-CoA reductase inhibitor. The term HMG-CoAreductase inhibitor is intended to include all pharmaceuticallyacceptable salt, ester, free acid and lactone forms of compounds whichhave HMG-CoA reductase inhibitory activity and, therefore, the use ofsuch salts, esters, free acids and lactone forms is included within thescope of this invention. Compounds which have inhibitory activity forHMG-CoA reductase can be readily identified using assays well-known inthe art. For instance, suitable assays are described or disclosed inU.S. Pat. No. 4,231,938 and WO 84/02131. Examples of suitable HMG-CoAreductase inhibitors include, but are not limited to, lovastatin(MEVACOR®; see, U.S. Pat. No. 4,231,938); simvastatin (ZOCOR®; see, U.S.Pat. No. 4,444,784); pravastatin sodium (PRAVACHOL®; see, U.S. Pat. No.4,346,227); fluvastatin sodium (LESCOL®; see, U.S. Pat. No. 5,354,772);atorvastatin calcium (LIPITOR®; see, U.S. Pat. No. 5,273,995) andrivastatin (also known as cerivastatin; see, U.S. Pat. No. 5,177,080).The structural formulas of these and additional HMG-CoA reductaseinhibitors that can be used in the methods of the present invention aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs,”Chemistry & Industry, pp. 85–89 (5 Feb. 1996). In presently preferredembodiments, the HMG-CoA reductase inhibitor is selected from lovastatinand simvastatin.

Dosage information for HMG-CoA reductase inhibitors is well known in theart, since several HMG-CoA reductase inhibitors are marketed in the U.S.In particular, the daily dosage amounts of the HMG-CoA reductaseinhibitor may be the same or similar to those amounts which are employedfor anti-hypercholesterolemic treatment and which are described in thePhysicians' Desk Reference (PDR). For example, see the 50th Ed. of thePDR, 1996 (Medical Economics Co); in particular, see at page 216 theheading “Hypolipidemics,” sub-heading “HMG-CoA Reductase Inhibitors,”and the reference pages cited therein. Preferably, the oral dosageamount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day and,more preferably, from about 5 to 160 mg/day. However, dosage amountswill vary depending on the potency of the specific HMG-CoA reductaseinhibitor used as well as other factors as noted above. An HMG-CoAreductase inhibitor which has sufficiently greater potency may be givenin sub-milligram daily dosages.

As examples, the daily dosage amount for simvastatin may be selectedfrom 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg,20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg;and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosageamount for atorvastatin calcium may be in the range of from 1 mg to 160mg and, more particularly, from 5 mg to 80 mg. Oral administration maybe in a single or divided doses of two, three, or four times daily,although a single daily dose of the HMG-CoA reductase inhibitor ispreferred.

The compounds of the present invention can be utilized in methods fordecreasing hyperglycemia and insulin resistance or for methods oftreating type II diabetes. The compounds can be identified, formulated,and administered as described above.

Diabetes mellitus, commonly called diabetes, refers to a disease processderived from multiple causative factors and characterized by elevatedlevels of plasma glucose, referred to as hyperglycemia. See, e.g.,LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincoft-RavenPublishers, Philadelphia, Pa. U.S.A. 1996). According to the AmericanDiabetes Association, diabetes mellitus is estimated to affectapproximately 6% of the world population. Uncontrolled hyperglycemia isassociated with increased and premature mortality due to an increasedrisk for microvascular and macrovascular diseases, includingnephropathy, neuropathy, retinopathy, hypertension, cerebrovasculardisease and coronary heart disease. Therefore, control of glucosehomeostasis is a critically important approach for the treatment ofdiabetes.

There are two major forms of diabetes: type 1 diabetes (formerlyreferred to as insulin-dependent diabetes or IDEM); and type 2 diabetes(formerly referred to as noninsulin dependent diabetes or NIDDM).

Type 2 diabetes is a disease characterized by insulin resistanceaccompanied by relative, rather than absolute, insulin deficiency. Type2 diabetes can range from predominant insulin resistance with relativeinsulin deficiency to predominant insulin deficiency with some insulinresistance. Insulin resistance is the diminished ability of insulin toexert its biological action across a broad range of concentrations. Ininsulin resistant individuals, the body secretes abnormally high amountsof insulin to compensate for this defect. When inadequate amounts ofinsulin are present to compensate for insulin resistance and adequatecontrol of glucose, a state of impaired glucose tolerance develops. In asignificant number of individuals, insulin secretion declines furtherand the plasma glucose level rises, resulting in the clinical state ofdiabetes. Type 2 diabetes can be due to a profound resistance to insulinstimulating regulatory effects on glucose and lipid metabolism in themain insulin-sensitive tissues: muscle, liver and adipose tissue. Thisresistance to insulin responsiveness results in insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. In Type 2 diabetes, freefatty acid levels are often elevated in obese and some non-obesepatients and lipid oxidation is increased.

Premature development of atherosclerosis and increased rate ofcardiovascular and peripheral vascular diseases are characteristicfeatures of patients with diabetes. Hyperlipidemia is an importantprecipitating factor for these diseases. Hyperlipidemia is a conditiongenerally characterized by an abnormal increase in serum lipids in thebloodstream and is an important risk factor in developingatherosclerosis and heart disease. For a review of disorders of lipidmetabolism, see, e.g., Wilson, J. et al., (ed.), Disorders of LipidMetabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W. B.Sanders Company, Philadelphia, Pa. U.S.A. 1998). Hyperlipidemia isusually classified as primary or secondary hyperlipidemia. Primaryhyperlipidemia is generally caused by genetic defects, while secondaryhyperlipidemia is generally caused by other factors, such as variousdisease states, drugs, and dietary factors. Alternatively,hyperlipidemia can result from both a combination of primary andsecondary causes of hyperlipidemia. Elevated cholesterol levels areassociated with a number of disease states, including coronary arterydisease, angina pectoris, carotid artery disease, strokes, cerebralarteriosclerosis, and xanthoma.

Dyslipidemia, or abnormal levels of lipoproteins in blood plasma, is afrequent occurrence among diabetics, and has been shown to be one of themain contributors to the increased incidence of coronary events anddeaths among diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med.(1927) 5: 1061–1079). Epidemiological studies since then have confirmedthe association and have shown a several-fold increase in coronarydeaths among diabetic subjects when compared with nondiabetic subjects(see, e.g., Garcia, M. J. et al., Diabetes (1974) 23: 105–11 (1974); andLaakso, M. and Lehto, S., Diabetes Reviews (1997) 5(4): 294–315).Several lipoprotein abnormalities have been described among diabeticsubjects (Howard B., et al., Arteriosclerosis (1978) 30: 153–162).

The term “insulin resistance” can be defined generally as a disorder ofglucose metabolism. More specifically, insulin resistance can be definedas the diminished ability of insulin to exert its biological actionacross a broad range of concentrations producing less than the expectedbiologic effect. (see, e.g., Reaven, G. M., J. Basic & Clin. Phys. &Pharm. (1998) 9: 387406 and Flier, J. Ann Rev. Med. (1983) 34:145–60).Insulin resistant persons have a diminished ability to properlymetabolize glucose and respond poorly, if at all, to insulin therapy.Manifestations of insulin resistance include insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. Insulin resistance can causeor contribute to polycystic ovarian syndrome, Impaired Glucose Tolerance(IGT), gestational diabetes, hypertension, obesity, atherosclerosis anda variety of other disorders. Eventually, the insulin resistantindividuals can progress to a point where a diabetic state is reached.The association of insulin resistance with glucose intolerance, anincrease in plasma triglyceride and a decrease in high-densitylipoprotein cholesterol concentrations, high blood pressure,hyperuricemia, smaller denser low-density lipoprotein particles, andhigher circulating levels of plasminogen activator inhibitor-1, has beenreferred to as “Syndrome X” (see, e.g., Reaven, G. M., Physiol. Rev.(1995) 75: 473486).

The term “diabetes mellitus” or “diabetes” means a disease or conditionthat is generally characterized by metabolic defects in production andutilization of glucose which result in the failure to maintainappropriate blood sugar levels in the body. The result of these defectsis elevated blood glucose, referred to as “hyperglycemia.” Type 2diabetes often occurs in the face of normal, or even elevated, levels ofinsulin and can result from the inability of tissues to respondappropriately to insulin. Most type 2 diabetic patients are insulinresistant and have a relative deficiency of insulin, in that insulinsecretion can not compensate for the resistance of peripheral tissues torespond to insulin. In addition, many type 2 diabetics are obese. Othertypes of disorders of glucose homeostasis include Impaired GlucoseTolerance, which is a metabolic stage intermediate between normalglucose homeostasis and diabetes, and Gestational Diabetes Mellitus,which is glucose intolerance in pregnancy in women with no previoushistory of type 1 or type 2 diabetes.

The term “complication” of diabetes includes, but is not limited to,microvascular complications and macrovascular complications.Microvascular complications are those complications which generallyresult in small blood vessel damage. These complications include, e.g.,retinopathy (the impairment or loss of vision due to blood vessel damagein the eyes); neuropathy (nerve damage and foot problems due to bloodvessel damage to the nervous system); and nephropathy (kidney diseasedue to blood vessel damage in the kidneys). Macrovascular complicationsare those complications which generally result from large blood vesseldamage. These complications include, e.g., cardiovascular disease andperipheral vascular disease. Cardiovascular disease refers to diseasesof blood vessels of the heart. See. e.g., Kaplan, R. M., et al.,“Cardiovascular diseases” in HEALTH AND HUMAN BEHAVIOR, pp. 206–242(McGraw-Hill, N.Y. 1993). Cardiovascular disease is generally one ofseveral forms, including, e.g., hypertension (also referred to as highblood pressure), coronary heart disease, stroke, and rheumatic heartdisease. Peripheral vascular disease refers to diseases of any of theblood vessels outside of the heart. It is often a narrowing of the bloodvessels that carry blood to leg and arm muscles.

The term “hyperlipidemia” refers to the presence of an abnormallyelevated level of lipids in the blood. Hyperlipidemia can appear in atleast three forms: (1) hypercholesterolemia, i.e., an elevatedcholesterol level; (2) hypertriglyceridemia, i.e., an elevatedtriglyceride level; and (3) combined hyperlipidemia, i.e., a combinationof hypercholesterolemia and hypertriglyceridemia.

The term “cholesterol” refers to a steroid alcohol that is an essentialcomponent of cell membranes and myelin sheaths and, as used herein,incorporates its common usage. Cholesterol also serves as a precursorfor steroid hormones and bile acids.

The term “triglyceride(s)” (“TGs”), as used herein, incorporates itscommon usage. TGs consist of three fatty acid molecules esterified to aglycerol molecule and serve to store fatty acids which are used bymuscle cells for energy production or are taken up and stored in adiposetissue.

The term “dyslipidemia” refers to abnormal levels of lipoproteins inblood plasma including both depressed and/or elevated levels oflipoproteins (e.g., elevated levels of LDL, VLDL and depressed levels ofHDL).

Exemplary Primary Hyperlipidemia include, but are not limited to, thefollowing:

(1) Familial Hyperchylomicronemia, a rare genetic disorder which causesa deficiency in an enzyme, LP lipase, that breaks down fat molecules.The LP lipase deficiency can cause the accumulation of large quantitiesof fat or lipoproteins in the blood;

(2) Familial Hypercholesterolemia, a relatively common genetic disordercaused where the underlying defect is a series of mutations in the LDLreceptor gene that result in malfunctioning LDL receptors and/or absenceof the LDL receptors. This brings about ineffective clearance of LDL bythe LDL receptors resulting in elevated LDL and total cholesterol levelsin the plasma;

(3) Familial Combined Hyperlipidemia, also known as multiplelipoprotein-type hyperlipidemia; an inherited disorder where patientsand their affected first-degree relatives can at various times manifesthigh cholesterol and high triglycerides. Levels of HDL cholesterol areoften moderately decreased;

(4) Familial Defective Apolipoprotein B-100 is a relatively commonautosomal dominant genetic abnormality. The defect is caused by a singlenucleotide mutation that produces a substitution of glutamine forarginine which can cause reduced affinity of LDL particles for the LDLreceptor. Consequently, this can cause high plasma LDL and totalcholesterol levels;

(5) Familial Dysbetaliproteinemia, also referred to as Type IIIHyperlipoproteinemia, is an uncommon inherited disorder resulting inmoderate to severe elevations of serum TG and cholesterol levels withabnormal apolipoprotein E function. HDL levels are usually normal; and

(6) Familial Hypertriglyceridemia, is a common inherited disorder inwhich the concentration of plasma VLDL is elevated. This can cause mildto moderately elevated triglyceride levels (and usually not cholesterollevels) and can often be associated with low plasma HDL levels.

Risk factors in exemplary Secondary Hyperlipidemia include, but are notlimited to, the following: (1) disease risk factors, such as a historyof type 1 diabetes, type 2 diabetes, Cushing's syndrome, hypothyroidismand certain types of renal failure; (2) drug risk factors, whichinclude, birth control pills; hormones, such as estrogen, andcorticosteroids; certain diuretics; and various .beta. blockers; (3)dietary risk factors include dietary fat intake per total caloriesgreater than 40%; saturated fat intake per total calories greater than10%; cholesterol intake greater than 300 mg per day; habitual andexcessive alcohol use; and obesity; and (4) non-genetic dyslipidemias.

The methods of the present invention can be used effectively incombination with one or more additional active diabetes agents dependingon the desired target therapy (see, e.g., Turner, N. et al. Prog. DrugRes. (1998) 51: 33–94; Haffner, S. Diabetes Care (1998)21: 160–178; andDeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Anumber of studies have investigated the benefits of combinationtherapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol.Metab. (1999) 84: 1165–71; United Kingdom Prospective Diabetes StudyGroup: UKPDS 28, Diabetes Care (1998) 21: 87–92; Bardin, C. W., (ed.),CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby—YearBook, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med.(1994) 121: 928–935; Coniff, R. et al., Clin. Ther. (1997) 19:16–26;Coniff, R. et al., Am. J. Med. (1995) 98: 443–451; and Iwamoto, Y. etal, Diabet. Med. (1996) 13 365–370; Kwiterovich, P. Am. J. Cardiol(1998) 82(12A): 3U–17U). These studies indicate that diabetes andhyperlipidemia modulation can be further improved by the addition of asecond agent to the therapeutic regimen.

An example of combination therapy that modulates (prevents the onset ofthe symptoms or complications associated) atherosclerosis, isadministered with one or more of the following active agents: anantihyperlipidemic agent; a plasma HDL-raising agent; anantihypercholesterolemic agent, such as a cholesterol biosynthesisinhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase inhibitor(also referred to as statins, such as lovastatin, simvastatin,pravastatin, fluvastatin, and atorvastatin), an HMG-CoA synthaseinhibitor, a squalene epoxidase inhibitor, or a squalene synthetaseinhibitor (also known as squalene synthase inhibitor); an acyl-coenzymeA cholesterol acyltransferase (ACAT) inhibitor, such as melinamide;probucol; nicotinic acid and the salts thereof and niacinamide; acholesterol absorption inhibitor, such as β-sitosterol; a bile acidsequestrant anion exchange resin, such as cholestyramine, colestipol ordialkylaminoalkyl derivatives of a cross-linked dextran; an LDL (lowdensity lipoprotein) receptor inducer; fibrates, such as clofibrate,bezafibrate, fenofibrate, and gemfibrizol; vitamin B₆ (also known aspyridoxine) and the pharmaceutically acceptable salts thereof, such asthe HCl salt; vitamin B₁₂ (also known as cyanocobalamin); vitamin B₃(also known as nicotinic acid and niacinamide, supra); anti-oxidantvitamins, such as vitamin C and E and beta carotene; a beta-blocker; anangiotensin II antagonist; an angiotensin converting enzyme inhibitor;and a platelet aggregation inhibitor, such as fibrinogen receptorantagonists (i.e., glycoprotein IIb/IIIa fibrinogen receptorantagonists) and aspirin.

Still another example of combination therapy can be seen in modulatingdiabetes (or treating diabetes and its related symptoms, complications,and disorders) with, for example, sulfonylureas (such as chlorpropamide,tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase,glimepiride, and glipizide), biguanides (such as metformin),thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, androsiglitazone); and related insulin sensitizers, such as selective andnon-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulfate ester, DHEA-SO₄); antiglucocorticoids; TNFα inhibitors;α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretogogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the active agents discussed above fortreating atherosclerosis.

Further provided by this invention are methods for treating obesity, aswell as treating the complications of obesity, by administering acompound of the present invention. The antagonists can be identified,formulated, and administered similarly to the information describedabove. A FXR selective antagonist includes a partial agonist/antagonistor antagonist that exhibits about a two to about a ten-fold preferencefor FXR compared to another nuclear receptor such as, for example LXR αor β with respect to potency (IC₅₀, the concentration of compound thatachieves 50% of the maximum reduction in the transcription activityachieved by the compound of interest observed in the presence of asub-maximal concentration of FXR agonist) and/or efficacy (the maximumpercent inhibition of transcription observed with the compound inquestion).

The terms “obese” and “obesity” refer to, according to the World HealthOrganization, a Body Mass Index (BMI) greater than 27.8 kg/m² for menand 27.3 kg/m² for women (BMI equals weight (kg)/height² (m²)). Obesityis linked to a variety of medical conditions including diabetes andhyperlipidemia. Obesity is also a known risk factor for the developmentof type 2 diabetes (See, e.g., Barrett-Conner, E., Epidemol. Rev. (1989)11: 172–181; and Knowler, et al., Am. J Clin. Nutr. (1991)53:1543–1551).

Another example of combination therapy can be seen in treating obesityor obesity-related disorders, wherein the methods can be effectivelyused in combination with, for example, phenylpropanolamine, phentermine,diethylpropion, mazindol; fenfluramine, dexfenfluramine, phentiramine,β₃ adrenoceptor agonist agents; sibutramine, gastrointestinal lipaseinhibitors (such as orlistat), and leptins. Other agents used intreating obesity or obesity-related disorders include neuropeptide Y,enterostatin, cholecytokinin, bombesin, amylin, histamine H₃ receptors,dopamine D₂ receptors, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

Another example of a combination therapy can be seen in treatingcholestasis, where the compounds of the invention can be combined withActigall (Ursodeoxycholic acid—UDCA), corticosteroids, anti-infectiveagents (Rifampin, Rifadin, Rimactane), anti-viral agents, Vitamin D,Vitamin A, phenobarbital, cholestyramine, UV light, antihistamines, oralopiate receptor antagonists and biphosphates, for the treatment,prevention, or amelioration of one or more symptoms of intrahepatic orextrahepatic cholestasis. Dosage information for these agents is wellknown in the art.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the subject matter claimedherein.

EXAMPLE 1 A. Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-one

To a 100 mL flask was added anhydrous anisole (14 mL),2-(methylthio)benzothiazole (10.0 g, 55.2 mmol) and methylp-toluenesulfonate (12.5 mL, 82.7 mmol). After heating the mixture at120° C. for 30 min, a crystalline solid precipitated. Anisole (14 mL)was added and the mixture was further heated at 120° C. for 4 h.

After cooling to room temperature, the mixture was then transferred to a1000 mL flask and diluted with anhydrous MeCN (200 mL). To thewell-stirred mixture was added N-benzyl rhodanine (12.3 g, 55.1 mmol)and then dropwise TEA (12.5 mL, 90 mmol). The resulting yellow slurrywas diluted with MeCN (200 mL) and stirred 2 h. The yellow precipitateswere filtered under reduced pressure, washed first with MeCN (50 mL) andthen MeOH (150 mL) to give the crude product.

To a three-neck 1 L flask fitted with a reflux condenser was added thecrude product, acetone (100 mL) and MeOH (200 mL). The mixture wasstirred under reflux for 15 min, cooled to room temperature, filteredunder reduced pressure, washed with MeOH (100 mL) and dried under vacuumfor 24 h to yield the title product (17.4 g, 85%) as a yellow solid,which was used without further purification. ¹H-NMR (CDCl₃): δ 7.61 (1H,dd), 7.55 (2H, m), 7.44 (1H, m), 7.25–7.34 (4H, m), 7.21 (1H, d), 5.37(2H, s), 3.91 (3H, s); MS(ESI): 371 (MH⁺).

B. Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate

To a 200 mL flask was added3-benzyl-5-(3-methylbenzothiazolin-2-ylidene)-2-thioxothiazolidin-4-one(5.00 g, 13.5 mmol), methyl p-toluenesulfonate (7.34 mL, 48.6 mmol) andanhydrous DMF(40 mL). After heating at 120° C. for 3 h, the mixture wasallowed to cool to 60° C., transferred to a 1 L flask and diluted withacetone (400 mL). After cooling to room temperature, the precipitate wasfiltered under reduced pressure, washed first with acetone (50 mL) andthen Et₂O (100 mL), and dried under vacuum for 12 h to give the titleproduct (6.25 g, 83%) as a yellow crystalline solid, which was usedwithout further purification. ¹H-NMR (CDCl₃): δ 7.83 (1H, d), 7.75 (2H,m), 7.59–7.66 (2H, m), 7.50 (1H, m), 7.37–7.43 (5H, m), 7.06 (2H, d),5.31 2H, s), 4.52 (3H, s), 3.22 (3H, s), 2.28 (3H, s).

C. Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-phenylimino-thiazolidine-4-one

To an 8 mL vial was added3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate (100 mg, 0.18 mmol), aniline (16 μL, 0.18 mmol) andanhydrous MeCN (1 mL). After warming the mixture to 50° C., TEA (0.10mL, 0.56 mmol) was added and continued heating the mixture at 50° C. for12 h. After cooling to room temperature, the resulting precipitates werefiltered under reduced pressure, washed with MeCN (2 mL) and dried undervacuum to yield the title product (22.3 mg, 29%) as a yellow solid.¹H-NMR (CDCl₃): δ 7.59 (2H, m), 7.48 (1H, dd), 7.26–7.39 (6H, m),7.10–7.18 (2H, m) 7.01 (3H, m), 5.16 (2H, s), 3.71 (3H, s); MS(ESI): 430(MH⁺).

EXAMPLE 2 Preparation of3-benzyl-2-(4-methoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-anisidine. ¹H-NMR (CDCl₃): δ 7.58(2H, d), 7.48 (1H, d), 7.26–7.35 (4H, m), 7.15 (1H, t), 7.01 (1H, d),6.96 (2H, d), 6.90 (2H, d), 5.16 (2H, s), 3.82 (3H, s), 3.73 (3H, s);MS(ESI): 460 (MH⁺).

EXAMPLE 3 Preparation of3-benzyl-2-(4-dimethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N,N-dimethyl-1,4-phenylendiamine.¹H-NMR (CDCl₃): δ 7.59 (2H, d), 7.47 (1H, d), 7.24–7.35 (4H, m), 7.14(1H, t), 6.99 (1H, d), 6.95 (2H, dd), 6.76 (2H, dd), 5.15 (2H, s), 3.73(3H, s), 2.95 (6H, s); MS(ESI): 473 (MH⁺).

EXAMPLE 4 Preparation of2-(4-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1,4-phenylenediamine. ¹H-NMR(CDCl₃): δ 7.58 (2H, m), 7.47 (1H, dd), 7.27–7.34 (4H, m), 7.14 (1H, m),6.99 (1H, d), 6.85 (2H, dd), 6.70 (2H, dd), 5.14 (2H, s), 3.72 (3H, s),3.60 (2H, br); MS(ESI): 445 (MH⁺).

EXAMPLE 5 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 6-aminoquinoline. ¹H-NMR (CDCl₃): δ8.84 (1H, dd), 8.09 (2H, d), 7.62 (2H, m), 7.50 (1H, d), 7.43 (1H, dd),7.27–7.40 (6H, m), 7.16 (1H, m), 7.01 (1H, d), 5.20 (2H, s), 3.69 (3H,s); MS(ESI): 481 (MH⁺).

EXAMPLE 6 Preparation of2-(2-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1,2-phenylenediamine. ¹H-NMR(CDCl₃): δ 7.48–7.56 (3H, m), 7.30–7.36 (3H, m), 7.26–29 (1H, m), 7.17(1H, t), 7.03 (1H, d), 6.91–6.99 (2H, m), 6.69–6.77 (2H, m), 5.19 (2H,s), 3.75 (3H, s), 3.49 (2H, s); MS(ESI): 445 (MH⁺).

EXAMPLE 7 Preparation of3-benzyl-2-(4-benzyloxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-benzyloxyaniline. ¹H-NMR (CDCl₃):δ 7.58 (2H, d), 7.43–7.50 (3H, m), 7.40 (2H, t), 7.26–7.36 (5H, m), 7.15(1H, t), 6.93–7.03 (5H, m), 5.14 (2H, s), 5.07 (2H, s), 3.73 (3H, s);MS(ESI): 536 (MH⁺).

EXAMPLE 8 Preparation of3-benzyl-2-(2-hydroxy-1-naphthylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-amino-2-naphthol hydrochloride.¹H-NMR (CDCl₃): δ 7.79 (1H, d), 7.56–7.64 (3H, m), 7.51 (2H, t),7.28–7.44 (6H, m), 7.21 (1H, d), 7.18 (1H, t), 6.99 (1H, d), 5.34 (2H,s), 5.00 (1H, s), 3.57 (3H, s); MS(ESI): 496 (MH⁺).

EXAMPLE 9 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-aminobenzonitrile. ¹H-NMR(DMSO-d₆): δ 7.72 (1H, d), 7.54 (2H, d), 7.23–7.41 (9H, m), 7.16–7.22(1H, m), 5.02 (2H, s), 3.74 (3H, s); MS(ESI): 455 (MH⁺).

EXAMPLE 10 Preparation of3-benzyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-aminothymol hydrochloride. ¹H-NMR(CDCl₃): δ 7.55–7.60 (2H, m), 7.48 (1H, d), 7.26–7.34 (4H, m), 7.14 (1H,m), 6.99 (1H, d), 6.76 (1H, s), 6.62 (1H, s), 5.17 (2H, s), 4.49 (1H,s), 3.71 (3H, s), 3.17 (1H, m), 1.96 (3H, s), 1.24 (6H, d); MS(ESI): 502(MH⁺).

EXAMPLE 11 Preparation of3-benzyl-2-(2-ethylamino-5-nitrophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N¹-ethyl-4-nitrobenzene-1,2-diamine.

¹H-NMR (CDCl₃): δ 7.98 (1H, dd), 7.93 (1H, d), 7.55 (1H, d), 7.44 (2H,d), 7.19–7.42 (6H, m), 7.11 (1H, d), 6.46 (1H, d), 5.20 (2H, s), 4.55(1H, br), 3.83 (3H, s), 3.07 (2H, m), 1.05 (3H, t); MS(ESI): 518 (MH⁺).

EXAMPLE 12 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[3-(trifluoromethyl)-phenylimino]thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-(trifluoromethyl)aniline. ¹H-NMR(CDCl₃): δ 7.57 (2H, m), 7.50 (1H, d), 7.46 (1H, t), 7.24–7.42 (6H, m),7.15–7.21 (2H, m), 7.03 (1H, d), 5.15 (2H, s), 3.73 (3H, s); MS(ESI):498 (MH⁺).

EXAMPLE 13 Preparation of2-(3-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3′-aminoacetophenone. ¹H-NMR(CDCl₃): δ 7.72 (1H, m), 7.56–7.60 (3H, m), 7.50 (1H, dd), 7.45 (1H, t),7.27–7.37 (4H, m), 7.21 (1H, ddd), 7.17 (1H, m), 7.02 (1H, d), 5.16 (2H,s), 3.72 (3H, s), 2.61 (3H, s); MS(ESI): 472 (MH⁺).

EXAMPLE 14 Preparation of3-benzyl-2-(3-chlorophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-chloroaniline. ¹H-NMR (CDCl₃): δ7.54–7.58 (2H, m), 7.49 (1H, dd), 7.26–7.36 (5H, m), 7.17 (1H, m), 7.09(1H, ddd), 7.03 (1H, d), 7.01 (1H, t), 6.89 (1H, ddd), 5.13 (2H, s),3.74 (3H, s); MS(ESI): 464 (MH⁺).

EXAMPLE 15 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-propyl-phenylimino)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 2-propylaniline. ¹H-NMR (CDCl₃): δ7.49 (1H, d), 7.27–7.37 (4H, m), 7.12–7.23 (3H, m), 7.06 (1H, m), 7.00(1H, d), 6.92 (1H, d), 5.17 (2H, s), 3.71 (3H, s), 2.37 (2H, t), 1.42(2H, s), 0.79 (3H, t); MS(ESI): 472 (MH⁺).

EXAMPLE 16 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoquinoline. ¹H-NMR (CDCl₃): δ8.86 (1H, d), 8.02 (1H, d), 7.81 (1H, d), 7.68 (1H, t), 7.42–7.50 (3H,m), 7.25–7.35 (5H, m), 7.20 (1H, d), 7.12 (1H, t), 7.07 (1H, d), 5.19(2H, s), 3.67 (3H, s); MS(ESI): 481 (MH⁺).

EXAMPLE 17 Preparation of3-benzyl-2-(2-ethoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with o-phenetidine. ¹H-NMR (CDCl₃): δ7.66 (2H, m), 7.46 (2H, d), 7.24–7.34 (3H, m), 7.07–7.16 (2H, m),6.94–7.00 (4H, m), 5.19 (2H, s), 4.01 (2H, q), 3.69 (3H, s), 1.36 (3H,t); MS(ESI): 474 (MH⁺).

EXAMPLE 18 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3′-aminoacetanilide. ¹H-NMR (CDCl₃):δ 7.57 (2H, d), 7.48 (1H, d), 7.27–7.39 (6H, m), 7.15 (2H, m), 7.06 (1H,br s), 7.01 (1H, d), 6.76 (1H, d), 5.14 (2H, s), 3.72 (3H, s), 2.18 (3H,s); MS(ESI): 487 (MH⁺).

EXAMPLE 19 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-aminobenzamide. ¹H-NMR (DMSO-d₆):δ 7.98 (1H, br s), 7.74 (1H, d), 7.62 (1H, d), 7.34–7.48 (9H, m), 7.30(1H, m), 7.21 (1H, m), 7.12 (1H, d), 5.06 (2H, s), 3.75 (3H, s);MS(ESI): 473 (MH⁺).

EXAMPLE 20 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicacid, methyl ester

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with methyl 3-aminobenzoate. ¹H-NMR(CDCl₃): δ 7.80 (1H, m), 7.68 (1H, m), 7.56–7.60 (2H, m), 7.49 (1H, dd),7.42 (1H, m), 7.27–7.36 (4H, m), 7.14–7.20 (2H, m), 7.01 (1H, d), 5.16(2H, s), 3.92 (3H, s), 3.71 (3H, s); MS(ESI): 488 (MH⁺).

EXAMPLE 21 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-3-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-aminopyridine. ¹H-NMR (CDCl₃): δ8.37 (1H, dd), 8.35 (1H, dd), 7.56–7.60 (2H, m), 7.51 (1H, dd),7.27–7.37 (6H, m), 7.18 (1H, m), 7.04 (1H, d), 5.16 (2H, s), 3.73 (3H,s); MS(ESI): 431 (MH⁺).

EXAMPLE 22 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethoxyphenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N-(4-amino-3-ethoxyphenyl)acetamide.

¹H-NMR (CDCl₃): δ 7.63 (2H, d), 7.48 (1H, d), 7.28–7.36 (5H, m), 7.15(1H, t), 7.10 (1H, s), 7.00 (1H, d), 6.96 (1H, d), 6.91 (1H, d), 5.18(2H, s), 3.97 (2H, q), 3.70 (3H, s), 2.16 (3H, s), 1.33 (3H, t);MS(ESI): 531 (MH⁺).

EXAMPLE 23 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-4-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-aminopyridine. ¹H-NMR (CDCl₃): δ8.53 (2H, dd), 7.56 (2H, m), 7.52 (1H, dd), 7.28–7.38 (4H, m), 7.19 (1H,m), 7.06 (1H, d), 6.93 (2H, dd), 5.14 (2H, s), 3.75 (3H, s); MS(ESI):431 (MH⁺).

EXAMPLE 24 Preparation of4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicacid, methyl ester

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with methyl 4-aminobenzoate. ¹H-NMR(CDCl₃): δ 8.04 (2H, m), 7.58 (2H, m), 7.50 (1H, d), 7.27–7.38 (4H, m),7.17 (1H, t), 7.01–7.08 (3H, m), 5.15 (2H, s), 3.92 (3H, s), 3.72 (3H,s); MS(ESI): 488 (MH⁺).

EXAMPLE 25 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[4-(trifluoro-methoxy)phenylimino]thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-(trifluoromethoxy)aniline. ¹H-NMR(CDCl₃): δ 7.57 (2H, m), 7.50 (1H, dd), 7.27–7.36 (4H, m), 7.14–7.22(3H, m), 7.03 (1H, d), 7.00 (2H, dd), 5.14 (2H, s), 3.75 (3H, s);MS(ESI): 514 (MH⁺).

EXAMPLE 26 Preparation of3-benzyl-2-(1H-indazol-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoindazole. ¹H-NMR (CDCl₃): δ10.05 (1H, br s), 8.08 (1H, d), 7.64–7.67 (2H, m), 7.51–7.55 (2H, m),7.32–7.41 (5H, m), 7.20 (1H, m), 7.14 (1H, dd), 7.04 (1H, d), 5.23 (2H,s), 3.74 (3H, s); MS(ESI): 470 (MH⁺).

EXAMPLE 27 Preparation of3-benzyl-2-(4-imidazol-1-ylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-(1H-imidazol-1-yl)aniline. ¹H-NMR(CDCl₃): δ 7.93 (1H, s), 7.66 (2H, d), 7.58 (1H, d), 7.35–7.46 (7H, m),7.29 (1H, s), 7.25 (1H, t), 7.18 (2H, m), 7.11 (1H, d), 5.24 (2H, s),3.82 (3H, s); MS(ESI): 496 (MH⁺).

EXAMPLE 28 Preparation of2-(benzo[1,3]dioxol-5-ylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3,4-(methylenedioxy)aniline. ¹H-NMR(CDCl₃): δ 7.56–7.60 (2H, m), 7.49 (1H, dd), 7.28–7.36 (4H, m), 7.16(1H, m), 7.02 (1H, d), 6.80 (1H, d), 6.56 (1H, d), 6.48 (1H, dd), 5.98(2H, s), 5.14 (2H, s), 3.75 (3H, s); MS(ESI): 474 (MH⁺).

EXAMPLE 29 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid

An aqueous solution of lithium hydroxide (1 M, 5 mL) was added to asolution of compound I-20 (0.13 g, 0.27 mmol) in THF (20 mL). Afterstirring at room temperature for 12 h, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was acidifiedwith hydrochloric acid (1 M, 10 mL) and extracted with EtOAc. Thecombined organic extracts were dried (anhydrous magnesium sulfate),concentrated under reduced pressure and chromatographed (silica gel,MeOH/DCM, 1:19) to yield the title compound (0.12 g, 95%) as a yellowsolid. ¹H-NMR (MeOD-d₃): δ 7.81 (1H, d), 7.63–7.68 (2H, m), 7.55 (1H,d), 7.50 (2H, d), 7.44 (1H, t), 7.31–7.40 (3H, m), 7.28 (1H, d),7.16–7.23 (3H, m), 5.15 (2H, s), 3.79 (3H, s); MS(ESI): 474 (MH⁺).

EXAMPLE 30 Preparation of N-ethyl-1,2-phenylenediamine

N-Ethyl-2-nitroaniline (0.97 g, 5.8 mmol) was dissolved in EtOAc (60 mL)and placed in a closed vessel. 10% Pd/C (0.4 g, 7 mol %) was added andthe mixture was hydrogenated under 50 psi H₂ for 2 h. The mixture wasfiltered through celite and the filtrate was concentrated under reducedpressure to yield the title product (0.79 g, 99%) as a brown liquid,which was used without further purification. ¹H-NMR (CDCl₃): δ 6.83 (1H,m), 6.64–6.74 (3H, m), 3.29 (3H, br s), 3.15 (2H, q), 1.30 (3H, t); TLC(2:98 MeOH/DCM R_(f) 0.24).

Preparation of3-benzyl-2-[2-(ethylamino)phenylimino]-5-(3-methyl-3H-benzethiazol-2-ylidene)thiazolidine-4-one

The title compound was then prepared in a manner similar to thatdescribed in Example 1 by replacing aniline withN-ethyl-1,2-phenylenediamine. ¹H-NMR (CDCl₃): δ 7.47–7.54 (3H, m),7.30–7.37 (3H, m), 7.28 (1H, m), 7.17 (1H, t), 7.00–7.06 (2H, m), 6.96(1H, dd), 6.64 (1H, m), 6.60 (1H, d), 5.19 (2H, s), 3.76 (3H, s), 3.68(1H, br s), 3.01 (2H, q), 1.05 (3H, t); MS(ESI): 473 (MH⁺).

EXAMPLE 31 Preparation of 4-methylamino-3-nitrobenzonitrile

4-Fluoro-3-nitrobenzonitrile (0.25 g, 1.5 mmol) was cautiously added toa solution of methylamine (2.0 M, 5.0 mL) in THF. The mixture wasstirred at room temperature for 8 h, concentrated under reducedpressure, and chromatographed (silica gel, DCM) to give the titleproduct (0.18 g, 68%) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.52 (1H, d),8.41 (1H, br s), 7.64 (1H, dd), 6.92 (1H, d), 3.10 (3H, d).

Preparation of 3-amino-4-(methylamino)benzonitrile

4-Methylamino-3-nitrobenzonitrile (0.18 g, 1.0 mmol) was dissolved inEtOAc (10 mL) and placed in a closed vessel. 10% Pd/C (50 mg, 5 mol %)was added and the mixture was hydrogenated via a hydrogen-filled balloonthat was affixed to the vessel. After 2 h the mixture was filteredthrough celite and the filtrate was concentrated under reduced pressureto yield the title product (0.14 g, 93%) as an off-white solid, whichwas used without further purification. ¹H-NMR (CDCl₃): δ 7.19 (1H, dd),6.92 (1H, d), 6.57 (1H, d), 4.04 (1H, br s), 3.30 (2H, br s), 2.91 (3H,br s); TLC (5:95 MeOH/DCM R_(f) 0.33).

Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile

The title compound was then prepared in a manner similar to thatdescribed in Example 1 by replacing aniline with3-amino-4-(methylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.55 (1H, d),7.42–7.47 (2H, m), 7.34–7.41 (3H, m), 7.28–7.34 (2H, m), 7.21 (1H, m),7.18 (1H, d), 7.11 (1H, d), 6.45 (1H, d), 5.17 (2H, s), 4.15 (1H, br s),3.83 (3H, s), 2.63 (3H, br s); MS(ESI): 484 (MH⁺).

EXAMPLE 32 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with ethylamine. ¹H-NMR (CDCl₃): δ7.54 (1H, d), 7.41–7.46 (2H, m), 7.27–7.40 (5H, m), 7.18–7.24 (2H, m),7.11 (1H, d), 6.49 (1H, d), 5.18 (2H, s), 4.23 (1H, t), 3.83 (3H, s),3.01 (2H, m), 1.02 (3H, t); MS(ESI): 498 (MH⁺).

EXAMPLE 33 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitril

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with isopropylamine. ¹H-NMR (CDCl₃):δ 7.54 (1H, d), 7.45 (2H, d), 7.27–7.40 (5H, m), 7.18–7.24 (2H, m), 7.11(1H, d), 6.53 (1H, d), 5.18 (2H, s), 4.29 (1H, d), 3.83 (3H, s), 3.54(1H, m), 1.02 (6H, d); MS(ESI): 512 (MH⁺).

EXAMPLE 34 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(dimethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with dimethylamine. ¹H-NMR (CDCl₃):δ 7.49–7.53 (3H, m), 7.27–7.37 (5H, m), 7.18 (1H, t), 7.13 (1H, d), 7.06(1H, d), 6.85 (1H, d), 5.18 (2H, s), 3.76 (3H, s), 2.68 (6H, s);MS(ESI): 498 (MH⁺).

EXAMPLE 35 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(tert-butylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with tert-butylamine. ¹H-NMR(CDCl₃): δ 7.54 (1H, d), 7.44 (2H, d), 7.27–7.40 (5H, m), 7.18–7.24 (2H,m), 7.11 (1H, d), 6.80 (1H, d), 5.18 (2H, s), 4.67 (1H, br s), 3.83 (3H,s), 1.22 (9H, s); MS(ESI): 526 (MH⁺).

EXAMPLE 36 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2,2,2-trifluoroethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with 2,2,2-trifluoroethylamine.¹H-NMR (CDCl₃): δ 7.57 (1H, d), 7.27–7.44 (8H, m), 7.23 (1H, t), 7.14(1H, d), 6.62 (1H, d), 5.17 (2H, s), 4.49 (1H, t), 3.86 (3H, s), 3.50(2H, m); MS(ESI): 552 (MH⁺).

EXAMPLE 37 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-piperidin-1-ylbenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with piperidine. ¹H-NMR (CDCl₃): δ7.50–7.54 (3H, m), 7.27–7.37 (5H, m), 7.18 (1H, t), 7.15 (1H, d), 7.05(1H, d), 6.92 (1H, d), 5.17 (2H, s), 3.75 (3H, s), 2.98 (4H, m), 1.44(6H, m); MS(ESI): 538 (MH⁺).

EXAMPLE 38 Preparation of2-[5-acetyl-2-(ethylamino)phenylimino]-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with ethylamine and by replacing4-fluoro-3-nitrobenzonitrile with 4′-chloro-3′-nitroacetophenone. ¹H-NMR(CDCl₃): δ 7.68 (1H, dd), 7.65 (1H, d), 7.53 (1H, d), 7.45–7.49 (2H, m),7.32–7.38 (3H, m), 7.28–7.31 (1H, m), 7.19 (1H, m), 7.06 (1H, d), 6.52(1H, d), 5.19 (2H, s), 4.24 (1H, t), 3.78 (3H, s), 3.06 (2H, m), 2.51(3H, s), 1.05 (3H, t); MS(ESI): 515 (MH⁺).

EXAMPLE 39 Preparation of3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing N-benzyl rhodanine with N-ethyl rhodanine. ¹H-NMR(CDCl₃): δ 7.63 (1H, d), 7.45 (1H, m), 7.30 (1H, m), 7.22 (1H, d), 4.24(2H, q), 3.91 (3H, s), 1.32 (3H, t); MS(ESI): 309 (MH⁺).

Preparation3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate

The title compound was prepared from3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-oneand methyl p-toluenesulfonate in a manner similar to that described inExample 1. ¹H-NMR (CDCl₃): δ 7.82 (1H, d), 7.77 (2H, d), 7.58–7.66 (2H,m), 7.49 (1H, m), 7.08 (2H, d), 4.52 (3H, s), 4.21 (2H, q), 3.29 (3H,s), 2.29 (3H, s), 1.45 (3H, t).

Preparation of3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)-thiazolidin-4-one

The title compound was prepared from3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate and 6-aminoquinoline in a manner similar to thatdescribed in Example 1. ¹H-NMR (CDCl₃): δ 8.85 (1H, dd), 8.11 (1H, d),8.10 (1H, d), 7.51 (1H, dd) 7.46 (1H, dd), 7.40 (1H, d), 7.38 (1H, dd),7.32 (1H, m), 7.16 (1H, m), 7.01 (1H, d), 4.10 (2H, q), 3.70 (3H, s),1.41 (3H, t); MS(ESI): 419 (MH⁺).

EXAMPLE 40 Preparation of3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-morpholin-4-yl-phenylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with 4-morpholin-4-ylaniline.¹H-NMR (CDCl₃): δ 7.49 (1H, dd), 7.31 (1H, m), 7.15 (1H, m), 6.91–7.02(5H, m), 4.03 (2H, q), 3.88 (4H, m), 3.73 (3H, s), 3.17 (4H, m), 1.36(3H, t); MS(ESI): 453 (MH⁺).

EXAMPLE 41 Preparation of3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(methylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.53 (1H, d),7.36 (1H, m), 7.36 (1H, dd), 7.25 (1H, m), 7.20 (1H, m), 7.09 (1H, d),6.60 (1H, d), 4.86 (1H, q), 4.07 (2H, q), 3.81 (3H, s), 2.92 (3H, d),1.37 (3H, t); MS(ESI): 422 (MH⁺).

EXAMPLE 42 Preparation of4-dimethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(dimethylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.52 (1H, dd),7.34 (1H, m), 7.34 (1H, dd), 7.20 (1H, d), 7.18 (1H, m), 7.06 (1H, d),6.92 (1H, d), 4.08 (2H, q), 3.76 (3H, s), 2.90 (6H, s), 1.38 (3H, t);MS(ESI): 436 (MH⁺).

EXAMPLE 43 Preparation of4-ethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(ethylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.53 (1H, d),7.32–7.40 (2H, m), 7.26 (1H, m), 7.20 (1H, m), 7.10 (1H, d), 6.60 (1H,d), 4.75 (1H, t), 4.08 (2H, q), 3.81 (3H, s), 3.22 (2H, m), 1.37 (3H,t), 1.29 (3H, t); MS(ESI): 436 (MH⁺).

EXAMPLE 44 Preparation of3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(isopropylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.53 (1H, dd),7.36 (1H, m), 7.32 (1H, dd), 7.25 (1H, d), 7.20 (1H, m), 7.10 (1H, d),6.60 (1H, d), 4.74 (1H, d), 4.08 (2H, q), 3.81 (3H, s), 3.67 (1H, m),1.37 (3H, t), 1.25 (6H, d); MS(ESI): 450 (MH⁺).

EXAMPLE 45 Preparation of3-(3-butyl-4-oxothiazolidin-2-ylideneamino)benzonitrile

To a 250 mL flask was added 3-aminobenzonitrile (0.59 g, 5.0 mmol),CHCl₃ (25 mL) and saturated sodium bicarbonate (25 mL). To thewell-stirred mixture was added dropwise thiophosgene (0.39 mL, 5.1mmol). After 2 h butylamine (0.50 mL, 5.1 mmol) was added dropwise andstirred 1 h. The reaction mixture was then extracted with CHCl₃,concentrated under reduced pressure, and chromatographed (silica gel,2:98 MeOH/DCM) to yield 1-butyl-3-(3-cyanophenyl)thiourea (1.02 g, 87%)as a white solid: TLC (2:98 MeOH/DCM R_(f) 0.47).

To a 100 mL flask was added anhydrous EtOH (25 mL),1-butyl-3-(3-cyanophenyl)thiourea (0.99 g, 4.2 mmol), ethylchloroacetate (0.51 mL, 5.0 mmol), and anhydrous pyridine (0.5 mL, 5mmol). After heating under reflux 16 h, the product mixture wasconcentrated under reduced pressure and chromatographed (silica gel,2:98 MeOH/DCM) to afford the title product (0.78 g, 67%) as a colorlessoil. ¹H-NMR (CDCl₃): δ 7.40–7.47 (2H, m), 7.25 (1H, m), 7.19 (1H, m),3.84 (2H, t), 3.84 (2H, s), 1.69 (2H, m), 1.39 (2H, m), 0.97 (3H, t);MS(ESI): 274 (MH⁺).

Preparation of3-[3-butyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

To a 8 mL vial was added3-(3-butyl-4-oxothiazolidin-2-ylideneamino)benzonitrile (55 mg, 0.20mmol), 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate (73mg, 0.20 mmol), anhydrous MeCN (2 mL) and TEA (70 μL, 0.50 mmol). Thereaction mixture was first warmed to 50° C. and the resulting solutionwas allowed to stir at room temperature for 16 h. The product mixturewas concentrated under reduced pressure, chromatographed (silica gel,1:99 MeOH/DCM) and then recrystallized from MeCN to give the titleproduct (11.8 mg) as a yellow solid.

¹H-NMR (CDCl₃): δ 7.52 (1H, dd), 7.38–7.48 (2H, m), 7.32–7.37 (2H, m),7.25 (1H, m), 7.18 (1H, m), 7.06 (1H, d), 3.96 (2H, t), 3.75 (3H, s),1.77 (2H, m), 1.44 (2H, m), 0.98 (3H, t); MS(ESI): 421 (MH⁺).

EXAMPLE 46 Preparation of3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-thioxothiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-(methylthio)benzothiazole with2-mercaptobenzoxazole. ¹H-NMR (CDCl₃): δ 7.49 (2H, d), 7.24–7.41 (6H,m), 7.18 (1H, d), 5.31(2H, s), 4.17 (3H, s); MS(ESI): 377 (MNa⁺).

Preparation of3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-(quinolin-5-ylimino)-thiazolidin-4-one

To a 10 mL flask was added3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-thioxothiazolidin-4-one(100 mg, 0.28 mmol), anhydrous CHCl₃ (2 mL) and methylp-toluenesulfonate (53 μL, 0.35 mmol). After heating at reflux 10 min,the reaction mixture was heated at 120° C. for 2 h to yield a red oil.The desired intermediate,3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate, was not isolated successfully in previousexperiments similar to Example 1 and, thus, the crude reaction mixturewas diluted with anhydrous CHCl₃ (4 mL) and used without purification inthe next step.

To a 8 mL vial was added the crude reaction mixture (2 mL) and5-aminoquinoline (29 mg, 0.20 mmol). After warming the mixture to 55°C., TEA (0.10 mL, 0.56 mmol) was added and the mixture was heated at 60°C. for 16 h. After cooling to room temperature, the resulting productmixture was concentrated under reduced pressure and chromatographed(silica gel, 2:98 MeOH/DCM) to yield the title product (21 mg) as ayellow solid. ¹H-NMR (CDCl₃): δ 8.86 (1H, dd), 7.97 (1H, dd), 7.85 (1H,d), 7.66 (1H, dd), 7.56 (2H, m), 7.30–7.42 (3H, m), 7.19–7.25 (3H, m),7.11–7.17 (2H, m), 7.05 (1H, d), 5.24 (2H, s), 4.11 (3H, s); MS(ESI):465 (MH⁺).

EXAMPLE 47 Preparation of3′-benzyl-3-methyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazol-yliden-4′-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-(methylthio)benzothiazole with2-mercapto-4-phenylthiazole. ¹H-NMR (CDCl₃): δ 7.49–7.56 (5H, m),7.34–7.38 (2H, m), 7.24–7.33 (3H, m), 6.54 (1H, s), 5.39 (2H, s), 3.68(3H, s); MS(ESI): 397 (MH⁺).

Preparation3′-benzyl-3-methyl-2′-methylthio-4′-oxo-4-phenyl-3H,4′H-[2,5′]bithiazol-yliden-3′-iump-toluenesulfonate

The title compound was prepared from3′-benzyl-3-methyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-oneand methyl p-toluenesulfonate in a manner similar to that described inExample 1. ¹H-NMR (CDCl₃): δ 7.72 (2H, d), 7.49–7.56 (3H, m), 7.42–7.47(2H, m), 7.36–7.41 (5H, m), 7.05 (2H, d), 6.99 (1H, s), 5.29 (2H, s),4.26 (3H, s), 3.14 (3H, s), 2.29 (3H, s).

Preparation ofN-[4-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)phenyl]acetamide

The title compound was prepared from3′-benzyl-3-methyl-2′-methylthio-4′-oxo-4-phenyl-3H,4′H-[2,5′]bithiazolyliden-3′-iump-toluenesulfonate and 4′-aminoacetanilide in a manner similar to thatdescribed in Example 1. ¹H-NMR (CDCl₃): δ 7.56 (2H, d), 7.42–7.47 (5H,m), 7.24–7.34 (5H, m), 7.12 (1H, s), 6.97 (2H, d), 6.30 (1H, s), 5.15(2H, s), 3.49 (3H, s), 2.17 (3H, s); MS(ESI): 513 (MH⁺).

EXAMPLE 48 Preparation of2′-[5-acetyl-2-(ethylamino)phenylimino]-3′-benzyl-3-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 47 by replacing 4′-aminoacetanilide with3′-amino-4′-(ethylamino)acetophenone. ¹H-NMR (CDCl₃): δ 7.63–7.67 (2H,m), 7.44–7.48 (5H, m), 7.27–7.37 (5H, m), 6.50 (1H, d), 6.37 (1H, s),5.20 (2H, s), 4.29 (1H, t), 3.55 (3H, s), 3.05 (2H, m), 2.49 (3H, s),1.04 (3H, t); MS(ESI): 541 (MH⁺).

EXAMPLE 49 Preparation of3-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazol-yliden-2′-ylideneamino)-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 47 by replacing 4′-aminoacetanilide with3-amino-4-(ethylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.46–7.50 (3H, m),7.41–7.45 (2H, m), 7.23–7.40 (6H, m), 7.21 (1H, d), 6.47 (1H, d), 6.40(1H, s), 5.18 (2H, s), 4.27 (1H, t), 3.59 (3H, s), 3.00 (2H, m), 1.01(3H, t); MS(ESI): 524 (MH⁺).

EXAMPLE 50 Preparation ofN-[4-(3′-benzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)phenyl]acetamide

The title compound was prepared in a manner similar to that described inExample 47 by replacing 2-mercapto-4-phenylthiazole with2-mercaptothiazole. ¹H-NMR (CDCl₃): δ 7.55 (2H, d), 7.44 (2H, d),7.24–7.33 (3H, m), 7.13 (1H, s), 6.95 (2H, d), 6.52 (1H, d), 6.37 (1H,d), 5.12 (2H, s) 3.68 (3H, s), 2.17 (3H, s); MS(ESI): 437 (MH⁺).

EXAMPLE 51 Preparation of N-[4-(3′-benzyl-3-methyl-4′-oxo-[2,5′]bithiazolidinyliden-2′-ylidene-amino)phenyl]acetamide

The title compound was prepared in a manner similar to that described inExample 47 by replacing 2-mercapto-4-phenylthiazole with2-methylthio-2-thiazoline. ¹H-NMR (CDCl₃): δ 7.53 (2H, d), 7.44 (2H, d),7.23–7.32 (3H, m), 7.14 (1H, s), 6.93 (2H, d), 5.07 (2H, s), 3.63 (2H,t), 3.16 (3H, s), 3.09 (2H, t), 2.17 (3H, s); MS(ESI): 439 (MH⁺).

EXAMPLE 52 Preparation of1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea

To a 100 mL flask was added 3-amino-4-(ethylamino)benzonitrile (1.0 g,6.2 mmol), anhydrous THF (50 mL) and benzylisothiocyanate (0.92 g, 6.2mmol). The reaction mixture was heated at 50° C. with stirring for 6 h.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex)to yield the title product (1.78 g, 93%). ¹H-NMR (CDCl₃): δ 7.48 (1H,dd), 7.37 (1H, d), 7.31 (3H, m), 7.24 (1H, s), 7.18 (1H, br), 6.67 (1H,d), 5.95 (1H, br), 4.81 (2H, d), 4.68 (1H, br), 3.19 (2H, m), 1.23 (3H,t).

Preparation of3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzo-nitrile

To a 100 mL flask was added1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.0 g, 3.2 mmol),anhydrous ethanol (40 mL), ethyl chloroacetate (0.39 g, 3.2 mmol) andthen DBU (0.58 g, 3.8 mmol). The reaction was heated at 80° C. for 30min. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure and chromatographed (silica gel, 1:1EtOAc/Hex) to afford the title product (0.98 g, 87%). ¹H-NMR (CDCl₃): δ7.38 (6H, m), 7.11 (1H, d), 6.50 (1H, d), 5.05 (2H, s), 3.96 (2H, s),3.01 (2H, m), 1.03 (3H, t).

Preparation of 3,5-dimethyl-4-phenyl-3H-thiazole-2-thione

To a 100 mL flask was added freshly prepared triethylammoniummethyldithiocarbamate (2.0 g, 9.5 mmol), anhydrous MeCN (50 mL), and2-bromopropiophenone (2.04 g, 9.5 mmol). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the resulting crude residue wastreated with conc H₂SO₄ (5 mL) with stirring at room temperature. After20 min, the reaction mixture was diluted with water (75 mL) and thenmixed with DCM (75 mL). The layers were separated and the aqueous layerextracted once more with DCM (75 mL). The combined organic layers werewashed with water (3×50 mL) and then brine (50 mL), dried over anhydrousMgSO₄ and concentrated under reduced pressure to afford the titleproduct (1.95 g, 92%) as an off-white solid, which was used withoutfurther purification. ¹H-NMR (CDCl₃): δ 7.50 (2H, m), 7.27 (2H, m), 3.45(3H, s), 2.06 (3H, s).

Preparation of3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile

To an 8 mL vial was added 3,5-dimethyl-4-phenyl-3H-thiazole-2-thione(100 mg, 0.45 mmol), methyl p-toluenesulfonate (126 mg, 0.68 mmol) andanhydrous anisole (0.5 mL). The reaction was heated to 120° C. andstirred for 3 h. The cooled reaction mixture was diluted with anhydrousMeCN (3 mL) and then treated with3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile(50 mg, 0.14 mmol) and TEA (70 μL, 0.50 mmol). The reaction mixture waswarmed to 80° C. and the resulting solution was allowed to stir for 16h. The product mixture was concentrated under reduced pressure andchromatographed (silica gel, 1:1 EtOAc/Hex) to yield the title product(48.3 mg, 64%) as a yellow solid. ¹H-NMR (CDCl₃): δ 7.40 (5H, m), 7.33(2H, m), 7.25 (3H, m), 7.23 (2H, m), 6.46 (1H, d), 5.18 (2H, s), 4.28(1H, m), 3.46 (3H, s), 2.99 (2H, m), 2.28 (3H, s), 1.01 (3H, t);MS(ESI): 538 (MH⁺).

EXAMPLE 53 Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

The FRET assay was performed by incubating 8 nM of GST-FXR-LBD, 8 nM ofEuropium-labeled anti-GST antibody (Wallac), 16 nM biotin-SRC-1 peptide[5′-biotin-CPSSHSSLTERHKILHRLLQEGSPS-CONH2], 20 nM APC-SA[allophycocyanin conjugated streptavidin] (Wallac) in FRET assay buffer(20 mM KH₂PO₄/K₂HPO₄ (pH 7.3), 150 mM NaCl, 2 mM CHAPS, 2 mM EDTA, 1 mMDTT) in the presence of the test compound(s) for 2–4 hours at roomtemperature. Data was collected using an LJL Analyst with readings at615 nm and 665 nm.

EXAMPLE 54 FXR Co-Transfection Assay

The basic co-transfection protocol for measuring FXR activity is asfollows. CV-1 African Green Monkey Kidney cells are plated 24 hoursbefore transfection to achieve approximately 70–80 percent confluency.Cells are transfected with CMX-hFXR, CMX-RXRα, Luc12 reporter(ECREx7-Tk-Luciferase), and a CMX-β-Galactosidase expression vector. Thetransfection reagent used is DOTAP. Cells are incubated with theDOTAP/DNA mixture for 5 hours after which the cells are harvested andplated onto either 96 well or 384 well plates containing the appropriateconcentration of test compound. The assay is allowed to continue for anadditional 18–20 hours, after which the cells are lysed, and theluciferase activity is measured on a standard plate reader.

Results of Examples 53 and 54

Both the FXR/ECREx7 co-transfection assay (Example 54) and the TR-FRETassay (Example 53) can be used to establish the EC₅₀/IC₅₀ values forpotency and percent activity or inhibition for efficacy. Efficacydefines the activity of a compound relative to a high control(chenodeoxycholic acid, CDCA) or a low control (DMSO/vehicle). The doseresponse curves are generated from an 8 point curve with concentrationsdiffering by ½ LOG units. Each point represents the average of 4 wellsof data from a 384 well plate. The curve for the data is generated byusing the equation:Y=Bottom+(Top−Bottom)/(1+10^((LogEC50−X)*HillSlope))

The EC₅₀/IC₅₀ is therefore defined as the concentration at which anagonist or antagonist elicits a response that is half way between theTop (maximum) and Bottom (baseline) values. The EC₅₀/IC₅₀ valuesrepresented are the averages of at least 3 independent experiments. Thedetermination of the relative efficacy or % control for an agonist is bycomparison to the maximum response achieved by chenodeoxycholic acidthat is measured individually in each dose response experiment.

For the antagonist assay, 40 μM CDCA is added to each well of a 384 wellplate to elicit a response. The % inhibition for each antagonist istherefore a measurement of the inhibition of the activity of 40 μM CDCA.In this example 100% inhibition would indicate that the activity of 40μM CDCA has been reduced to baseline levels, defined as the activity ofthe assay in the presence of DMSO only.

Most of the compounds disclosed herein and tested exhibited activity inat least one of the above assays (EC₅₀ or IC₅₀ less than 10 μM). Mostshowed activity at below 1 μM. Some showed activity below 100 nM. Forexample,3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile(Example 32) shows an EC₅₀ of about 0.010 μM and a % efficacy of about150% in the co-transfection assay; and3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile(Example 52) shows an EC₅₀ of about 0.056 μM and a % efficacy of about32% in the co-transfection assay; and an IC₅₀ of about 0.042 μM and a %inhibition of about 48% in a FRET assay.

EXAMPLE 55 Preparation of3{3-benzyl-5-[3-methyl-5-(trifluoromethyl)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitril

To a suspension of 2-amino-4-(trifluoromethyl)benzenethiol hydrochloride(4.58 g, 20 mmol) in CHCl₃ (50 mL) was added saturated aqueous Na₂CO₃(50 mL). To this stirred biphasic mixture was added CSCl₂ (1.57 mL, 20mmol) dropwise. After the addition was complete, the mixture was stirredfor 72 h at 20° C. The organic layer was separated and the aqueous layerwas extracted by CHCl₃ (3×20 mL). The combined organic layer was washedby water and dried over MgSO₄. Evaporation of solvent gave2-mercapto-5-(trifluoromethyl)benzothiazole (1.27 g), which was used inthe next step without further purification. ¹H-NMR (CDCl₃): δ 7.23 (1H,d), 6.94 (1H, s), 6.81 (1H, d), 4.53 (s, 1H).

To a suspension of the above compound in anisole (10 mL) was addedmethyl tosylate (MeOTs) (2.5 mL, 2 equiv) and the suspension was heatedto 130° C. for 3 h. After cooling to 20° C., acetonitrile and3-benzylrhodanine were added. To this suspension was added TEA (3 mL, 4equiv) dropwise, yellow precipitate appeared immediately. The suspensionwas stirred for 5 h at 20° C. The yellow solid was collected byfiltration and washed by acetonitrile and dried under high vacuum togive the product (360 mg).

To a suspension of the above compound in DMF (4 mL) was added MeOTs(0.45 mL, 3 equiv) and the resulted suspension was heated to 130° C. for5 h. After cooling to 20° C., acetone was added to precipitate theproduct. Solid was collected by filtration and washed by acetone anddried under high vacuum to afford the tosylate salt (110 mg).

A mixture of the above compound (56 mg, 0.1 mmol),3-amino-4-(ethylamino)benzonitrile (16 mg, 0.1 mmol) and TEA (28 μL, 0.2mmol) was shaken at 60° C. overnight. Evaporation of solvent gave acrude, which was purified by trituration with MeOH to afford the titlecompound (27 mg). ¹H-NMR indicated one isomer. ¹H-NMR (CDCl₃): δ 7.61(1H, d), 7.44 (2H, m), 7.35 (2H, m), 7.27–7.31 (4H, m), 7.18 (1H), 6.5(1H), 5.19 (2H, s), 4.19 (1H, t), 3.84 (3H, s), 3.01 (2H, m), 1.03 (3H,t); MS (ESI): 566 (MH⁺).

EXAMPLE 56 Preparation of3-[3-benzyl-5-(3-methyl-5-methoxy-3H-benzothiazol-2-ylidene)4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by starting from 2-mercapto-5-methoxy-benzothiazole. ¹H-NMRindicated one isomer. ¹H-NMR (DMSO-d₃): δ 7.47 (1H, d), 7.13–7.21 (5H,m), 6.98 (1H, d), 6.86 (1H, d), 6.67 (1H, dd), 6.46 (1H, d), 4.96 (2H,s), 4.81 (1H, m), 3.66 (3H, s), 3.65 (3H, s), 2.89 (2H, m), 0.83 (3H,t); MS (ESI): 528 (MH⁺).

EXAMPLE 57 Preparation of3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

To a suspension of the product of Example 56 (1.06 g, 2 mmol) in DCM (10mL) was added BBr₃ (1.0 M in DCM, 2 mL) dropwise at −78° C. It waswarmed to 20° C. slowly and the suspension was stirred for 72 h at 20°C. under N₂. MeOH was added to decompose BBr₃ at 0° C. Solvent wasremoved to give a crude, which was purified by chromatography on silicagel eluting with MeOH-DCM (2.5:97.5) to afford the title compound (0.6g). ¹H-NMR indicated one isomer. ¹H-NMR (DMSO-d₆): δ 9.66 (1H, s), 7.35(1H, d), 7.13–7.24 (5H, m), 6.99 (1H, d), 6.60 (1H, d), 6.53 (1H, dd),6.46 (1H, d), 4.96 (2H, s), 4.82(1H, t), 3.58 (3H, s), 2.89 (2H, m),0.84 (3H, t); MS (ESI): 514 (MH⁺).

EXAMPLE 58 Preparation of Dimethylcarbamic acid2-[3-benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylester

To a suspension of the product of Example 57 in CHCl₃ was added TEA (84μL, 0.6 mmol) and dimethylcarbamoyl chloride (56 μL, 0.6 mmol). Theresulting suspension was heated to 65° C. overnight with shaking.Solvent was removed under vacuum to give a crude, which was purified bychromatography on silica gel, eluting by MeOH-DCM (5:95) to afford thetitle compound (38.6 mg). ¹H-NMR indicated one isomer. ¹H-NMR (DMSO-d₆):δ 97.73 (1H, d), 7.28–7.39 (7H, m), 7.14 (1H, d), 6.97 (1H, dd), 6.63(1H, dd), 5.12 (2H, s), 4.98(1H, t), 3.78 (3H, s), 3.05 (6H, m), 2.91(3H, s), 0.99 (3H, t); MS (ESI): 585 (MH⁺).

EXAMPLE 59 Preparation of3-{3-benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

To a solution of the product of Example 57 in DMF were added K₂CO₃ and3-bromoethanol and the resulting suspension was heated to 75° C. withstirring under nitrogen for 72 h. Solid was removed by filtration andwashed by DMF. Evaporation of solvent gave a crude, which was purifiedby chromatography on silica gel eluting with MeOH-DCM (5:95) to affordthe title compound (0.58 g). ¹H-NMR indicated one isomer. ¹H-NMR(DMSO-d₆): δ 7.62 (1H, d), 7.29–7.39 (5H, m), 7.14 (1H, d), 7.02 (1H,d), 6.84 (1H, dd), 5.75 (1H, d), 5.11 (2H, s), 4.97 (1H, t), 4.87(1H,t), 4.05 (2H, t), 3.80 (3H, s), 3.71 (2H, m), 3.05 (2H, m), 0.99 (3H,t); MS (ESI): 558 (MH⁺).

EXAMPLE 60 Preparation of3-{3-benzyl-5-[3-methyl-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

To a suspension of the product of Example 59 (56 mg, 0.1 mmol) inanhydrous DCM (2 mL) was added triflic anhydride (Tf₂O) at −10° C. undernitrogen. The suspension was stirred for 1 h at −10° C. Morpholine (44μL, 0.5 mmol) was added and the reaction mixture was stirred overnightat 20° C. Evaporation of solvent gave a crude, which was purified bychromatography on silica gel eluting with MeOH-DCM to give the titlecompound (18 mg). ¹H-NMR indicated one isomer. ¹H-NMR (CDCl₃): δ 7.44(2H, m), 7.39 (1H, d), 7.32–7.36 (2H, m), 7.27–7.30 (2H, m), 7.20 (1H,d), 6.78 (1H, dd), 6.67 (1H, d), 6.49 (1H, d), 5.17 (2H, s), 4.22 (1H,t), 4.15 (2H, t), 3.78 (3H, s), 3.75 (4H, m), 3.01 (2H, m), 2.83 (2H,t), 2.59 (2H, t), 1.02 (3H, t); MS (ESI): 627 (MH⁺).

EXAMPLE 613-[3-benzyl-5-(1,3-dimethyl-1,3-dihydrobenzoimidazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

To a suspension of 2-mercaptobenzimidazole (15.02 g, 100 mmol) inaqueous NaHCO₃ (25.2 g, 300 mmol in 40 mL of H₂O) was added Me₂SO₄ (47.4mL, 500 mmol) dropwise at 20° C. A clear solution was obtained. Thesolution was stirred for 17 h at 20° C. NaI (3.2 g, 200 mmol) was added.After the solution was cooled in an ice-water bath, yellowishprecipitate appeared. Solid was collected by filtration and washed bycold water and ether. Drying under high vacuum afforded the iodide salt(6.5 g).

To a solution of the above salt (66 mg, 0.2 mmol) and3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile(70 mg, 0.2 mmol) in DMF was added DBU (62 mL, 2 equiv) and the solutionwas heated to 100° C. for 48 h. Evaporation of solvent under high vacuumgave a crude, which was purified by chromatography on silica gel elutingwith EtOAc-hexane (1:1) to give the title compound (3.6 mg). ¹H-NMRindicated one isomer. ¹H-NMR (CDCl₃): δ 7.46 (2H, m), 7.22–7.36 (8H, m),6.46 (1H, d), 5.17 (2H, s), 4.44 (1H, t), 3.79 (3H, s), 3.01 (2H, m),0.88 (3H, t); MS (ESI): 495 (MH⁺).

EXAMPLE 62 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-8-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 8-aminoquinoline. MS(ESI): 481(MH⁺).

EXAMPLE 63 Preparation of3-benzyl-2-(8-hydroxyquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoquinolin-8-ol. MS(ESI): 497(MH⁺).

EXAMPLE 64 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-butylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with butylamine. MS(ESI): 526 (MH⁺).

EXAMPLE 65 Preparation of4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with benzylamine. MS(ESI): 560(MH⁺).

EXAMPLE 66 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyclopentylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with cyclopentylamine. MS(ESI): 538(MH⁺).

EXAMPLE 67 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(pyrrolidin-1-ylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with 1-aminopyrrolidine. MS(ESI):539 (MH⁺).

EXAMPLE 68 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-pyrrolidin-1-ylbenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with pyrrolidine. MS(ESI): 524(MH⁺).

EXAMPLE 69 Preparation of3-benzyl-2-(isoquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoisoquinoline. MS(ESI): 481(MH⁺).

EXAMPLE 70 Preparation of3-benzyl-2-(isoquinolin-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-aminoisoquinoline. MS(ESI): 481(MH⁺).

EXAMPLE 71 Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4′-aminoacetanilide. MS(ESI): 487(MH⁺).

EXAMPLE 72 Preparation of2-(4-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4′-aminoacetophenone. MS(ESI): 482(MH⁺).

EXAMPLE 73 Preparation of4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-aminobenzamide. MS(ESI): 473(MH⁺).

EXAMPLE 74 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-1-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-naphthylamine. MS(ESI): 480 (MH⁺).

EXAMPLE 75 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-2-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 2-naphthylamine. MS(ESI): 480 (MH⁺).

EXAMPLE 76 Preparation of3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-2-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-aminopyridine. MS(ESI): 431 (MH⁺).

EXAMPLE 77 Preparation of4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4′-aminobenzenesulfonamide. MS(ESI):509 (MH⁺).

EXAMPLE 78 Preparation ofN-acetyl-4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N-acetyl-4-aminobenzenesulfonamide.MS(ESI): 551 (MH⁺).

EXAMPLE 79 A. Preparation of2-(3-acetylphenylimino)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared from 3-picolyl isothiocyanatehydrobromide and 3′-aminoacetophenone in a manner similar to Example 52.

¹H-NMR (CDCl₃): δ 8.80 (1H, d), 8.58 (1H, dd), 7.85 (1H, m), 7.74 (1H,m), 7.54 (1H, m), 7.45 (1H, m), 7.29 (1H, m), 7.15 (1H, m), 5.05 (2H,s), 3.86 (2H, s), 2.60 (3H, s).

B. Preparation of2-(3-acetylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared from intermediate2-(3-acetylphenylimino)-3-pyridin-3-ylmethylthiazolidin-4-one and3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate asdescribed in Example 45. ¹H-NMR (CDCl₃): δ 8.87 (1H, d), 8.56 (1H, dd),7.93 (1H, m), 7.74 (1H, m), 7.60 (1H, m), 7.53 (1H, d), 7.46 (1H, m),7.27–7.38 (2H, m), 7.17–7.23 (2H, m), 7.05 (1H, d), 5.18 (2H, s), 3.74(3H, s), 2.62 (3H, s); MS(ESI): 473 (MH⁺).

EXAMPLE 80 A. Preparation of N-(5-nitropyridin-2-yl)acetamide

To a hot solution of 2-amino-5-nitropyridine (1.4 g, 10 mmol) in aceticanhydride (5 mL) at 100° C. was added conc. H₂SO₄ (0.1 mL). Theresulting mixture was heated at 130° C. for 2 h, cooled and partitionedbetween EtOAc (200 mL) and water (100 mL). The layers were separated andthe aqueous layer was washed once with EtOAc (100 mL). The combinedorganic layers were washed with water (100 mL), saturated aqueous NaHCO₃(100 mL) and then brine (50 mL); dried over anhydrous MgSO₄ andconcentrated under reduced pressure to affordN-(5-nitropyridin-2-yl)acetamide (1.8 g, 98%), which was used withoutfurther purification. ¹H-NMR-(CDCl₃): δ 9.14 (1H, d), 8.50 (1H, dd),8.40 (1H, d), 8.23 (1H, br s), 2.29 (3H, s).

B. Preparation ofN-{5-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]pyridin-2-yl}acetamide

In a manner similar to Example 30, intermediateN-(5-nitropyridin-2-yl)acetamide was hydrogenated and then condensedwith3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (DMSO-d₆): δ10.45 (1H, s), 8.07 (1H, d), 7.97 (1H, d), 7.75 (1H, d), 7.33–7.46 (7H,m), 7.29 (1H, m), 7.22 (1H, m), 5.06 (2H, s), 3.79 (3H, s), 2.09 (3H,s); MS(ESI): 488 (MH⁺).

EXAMPLE 81 Preparation ofN-{5-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5′-amino-2′-cyanoacetanilide.MS(ESI): 512 (MH⁺).

EXAMPLE 82 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 79 by replacing 3′-aminoacetophenone with3′-amino-4′-(ethylamino)acetophenone. MS(ESI): 516 (MH⁺).Recrystallization of the product from hot ethanol afforded crystalssuitable for single-crystal X-ray diffraction. Structural analysisshowed that the E-isomer had been obtained.

EXAMPLE 83 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 79 by replacing 3′-aminoacetophenone with3-amino-4-(ethylamino)benzonitrile. MS(ESI): 499 (MH⁺).

EXAMPLE 84 Preparation of4-ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with2-furfuryl isothiocyanate. MS(ESI): 488 (MH⁺).

EXAMPLE 85 Preparation of2-(5-acetyl-2-methylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 31 by replacing 4-fluoro-3-nitrobenzonitrile with4′-chloro-3′-nitroacetophenone. MS(ESI): 501 (MH⁺).

EXAMPLE 86 Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2,2,2-trifluoroacetamide

The product of Example 4 was treated with trifluoroacetic anhydride inanhydrous DCM. After 1 h the product mixture was diluted with EtOAc,washed with water and satd aqueous NaHCO₃, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the title compound asa yellow solid. ¹H-NMR (CDCl₃): δ 7.81 (1H, br s), 7.53–7.59 (4H, m),7.49 (1H, d), 7.27–7.36 (4H, m), 7.17 (1H, m), 7.01–7.06 (3H, m), 5.15(2H, s), 3.73 (3H, s); MS(ESI): 541 (MH⁺).

EXAMPLE 87 A. Preparation of 4-ethylamino-3-nitrobenzoic acid methylester

In a manner similar to Example 31, 4-fluoro-3-nitrobenzoic acid wastreated with ethylamine to give 4-ethylamino-3-nitrobenzoic acid, whichwas then esterified with anhydrous hydrogen chloride in methanol to givethe title compound. ¹H-NMR (CDCl₃): δ 8.89 (1H, d), 8.28 (1H, br s),8.06 (1H, dd), 6.87 (1H, d), 3.90 (3H, s), 3.42 (2H, m), 1.40 (3H, t).

B. Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoicacid methyl ester

In a manner similar to Example 30, intermediate4-ethylamino-3-nitrobenzoic acid methyl ester was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.73(1H, dd), 7.65 (1H, d), 7.52 (1H, dd), 7.45–7.49 (2H, m), 7.27–7.38 (4H,m), 7.18 (1H, m), 7.06 (1H, d), 6.52 (1H, d), 5.19 (2H, s), 4.14 (1H, brt), 3.85 (3H, s), 3.78 (3H, s), 3.04 (2H, m), 1.04 (3H, t); MS(ESI): 531(MH⁺).

EXAMPLE 88 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenethylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide withphenethyl isothiocyanate. MS(ESI): 512 (MH⁺).

EXAMPLE 89 Preparation of2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicacid

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with anthranilic acid. MS(ESI): 474(MH⁺).

EXAMPLE 90 A. Preparation of 4-ethylamino-3-nitrobenzoic acid tert-butylester

4-Chloro-3-nitrobenzoic acid tert-butyl ester (3.0 g, 11.6 mmol),prepared according to a published procedure [WO 9707101], was cautiouslyadded to a solution of 2.0 M EtNH₂/THF (20 mL, 40 mmol) and TEA (2.0 mL,14 mmol) in anhydrous THF (30 mL). The resulting mixture was heated at65° C. for 3 h, cooled, concentrated under reduced pressure, dilutedwith DCM (200 mL), washed with water (2×100 mL) and brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated to give the title compound (3.1g, 99%) as a yellow solid, which was used without further purification.¹H-NMR (CDCl₃): δ 8.80 (1H, d), 8.24 (1H, br s), 8.02 (1H, dd), 6.84(1H, d), 3.41 (2H, m), 1.59 (9H, s), 1.40 (3H, t).

B. Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoicacid tert-butyl ester

In a manner similar to Example 30, intermediate4-ethylamino-3-nitrobenzoic acid tert-butyl ester was hydrogenated andthen condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.69(1H, dd), 7.61 (1H, d), 7.52 (1H, dd), 7.45–7.49 (2H, m), 7.27–7.37 (4H,m), 7.18 (1H, m), 7.06 (1H, d), 6.51 (1H, d), 5.19 (2H, s), 4.11 (1H, brt), 3.79 (3H, s), 3.04 (2H, m), 1.57 (9H, s), 1.04 (3H, t); MS(ESI): 573(MH⁺).

EXAMPLE 91 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoicacid

The product of Example 90 was treated with 55% TFA/DCM for 1 h,concentrated under reduced pressure, diluted with DCM, concentrated onceagain, diluted with DCM, allowed to stand over solid NaHCO₃, filteredand concentrated to afford the title product. MS(ESI): 517 (MH⁺).

EXAMPLE 92 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-hydroxyethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with 2-aminoethanol. ¹H-NMR (CDCl₃):δ 7.52 (1H, d), 7.42–7.49 (4H, m), 7.27–7.37 (4H, m), 7.19 (1H, m), 7.05(1H, d), 6.57 (1H, d), 5.94 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.48(2H, m), 3.03 (2H, q), 1.23 (3H, t), 1.04 (3H, t); MS(ESI): 514 (MH⁺).

EXAMPLE 93 Preparation of{2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}aceticacid methyl ester

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with glycine methyl ester. MS(ESI):542 (MH⁺).

EXAMPLE 94 A. Preparation of N-ethyl-4-ethylamino-3-nitrobenzamide

In a manner similar to Example 31, the title compound was prepared from4-fluoro-3-nitrobenzoic acid (as a mixed anhydride) and ethylamine.¹H-NMR (CDCl₃): δ 8.52 (1H, d), 8.21 (1H, br s), 7.98 (1H, dd), 6.90(1H, d), 6.06 (1H, br s), 3.46–3.57 (2H, m), 3.38–3.45 (2H, m), 1.40(3H, t), 1.27 (3H, t).

B. Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-4-ethylaminobenzamide

In a manner similar to Example 30, intermediateN-ethyl-4-ethylamino-3-nitrobenzamide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 544 (MH⁺).

EXAMPLE 95 Preparation of{2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}aceticacid

The product of Example 93 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 528(MH⁺).

EXAMPLE 96 A. Preparation of 4-ethylamino-3-nitropyridine

In a manner similar to example 31, the title compound was prepared from4-chloro-3-nitropyridine, prepared according to published procedure [J.Med. Chem. 1996, 39, 487–493], and ethylamine. ¹H-NMR (CDCl₃): δ 9.22(1H, s), 8.30 (1H, d), 8.10 (1H, br s), 6.71 (1H, d), 3.40 (2H, m), 1.39(3H, t).

B. Preparation of3-benzyl-2-(4-ethylaminopyridin-3-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

In a manner similar to Example 30, intermediate4-ethylamino-3-nitropyridine was hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ8.04–8.09 (2H, m), 7.53 (1H, d), 7.44–7.48 (2H, m), 7.27–7.38 (4H, m),7.19 (1H, m), 7.07 (1H, d), 6.42 (1H, d), 5.19 (2H, s), 4.12 (1H, br t),3.79 (3H, s), 3.02 (2H, m), 1.05 (3H, t); MS(ESI): 474 (MH⁺).

EXAMPLE 97 A. Preparation of 3′-fluoro-4′-nitroacetanilide

Added 3′-fluoroacetanilide (3.06 g, 20 mmol) cautiously to concentratedsulfuric acid (6 mL) at 5° C. To the resulting solution, added fumingnitric acid (1.05 mL, 25 mmol) dropwise while maintaining temperature at5–10° C. After 30 min, added ice (50 g), later diluted with water (100mL) and extracted with EtOAc (2×100 mL). The combined organic layerswere washed with saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄and concentrated to give the crude product (4.0 g) as a mixture ofisomers (1:1.4 ratio of 4′-nitro/2′-nitro). The desired isomer,3′-flouro-4′-nitroacetanilide, was isolated by flash chromatography(DCM-5% MeOH/DCM) in low yield (1.2 g, 30%) as a yellow solid. ¹H-NMR(CDCl₃): δ 8.08 (1H, app t), 7.82 (1H, dd), 7.41 (1H, br s), 7.21 (1H,m), 2.25 (3H, s).

B. Preparation of 3′-ethylamino-4′-nitroacetanilide

In a manner similar to Example 31, the title compound was prepared from3′-fluoro-4′-nitroacetanilide and ethylamine. ¹H-NMR (CDCl₃): δ 8.17(1H, brs), 8.13 (1H, d), 7.57 (1H, br d), 7.33 (1H, brs), 6.38 (1H, dd),3.36 (2H, m), 2.22 (3H, s), 1.37 (3H, t).

C. Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-3-ethylaminophenyl}acetamide

In a manner similar to Example 30, intermediate3′-ethylamino-4′-nitroacetanilide was hydrogenated and then condensedwith3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ7.45–7.53 (3H, m), 7.27–7.37 (4H, m), 7.17 (1H, m), 7.03–7.09 (2H, m),6.91 (1H, d), 6.83 (1H, br d), 6.75 (1H, brs), 5.18 (2H, s), 3.78 (3H,s), 2.99 (2H, m), 2.15 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH⁺).

EXAMPLE 98 Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-dimethylaminoethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with N,N-dimethylethylenediamine.MS(ESI): 541 (MH⁺).

EXAMPLE 99 A. Preparation of N-ethyl-3-ethylamino-4-nitrobenzamide

To a chilled solution (10° C.) of 3-fluoro-4-nitrobenzoyl chloride (1.0g, 4.9 mmol) in anhydrous THF (30 mL) added dropwise 2.0 M solution ofethylamine in THF (10 mL, 20 mmol). After stirring 16 h at 25° C.,combine with saturated NaHCO₃ (50 mL) and extracted with EtOAc (3×80mL). The combined organic layers were washed with 1 N NaOH (50 mL) andbrine (50 mL), dried over anhydrous MgSO₄ and concentrated under reducedpressure to yield the title compound (0.66 g, 57%) as an orange-yellowsolid that was used without further purification. ¹H-NMR (CDCl₃): δ8.20(1H, d), 7.98(1H, br s), 7.36 (1H, d), 6.81 (1H, dd), 6.13 (1H, brs), 3.51 (2H, m), 3.42 (2H, m), 1.39 (3H, t), 1.27 (3H, t).

B. Preparation of4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-3-ethylaminobenzamide

In a manner similar to Example 30, intermediateN-ethyl-3-ethylamino-4-nitrobenzamide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ7.46–7.54 (3H, m), 7.27–7.38 (4H, m), 7.19 (1H, m), 6.96–7.08 (4H, m),6.04 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.49 (2H, m), 3.06 (2H, q),1.25 (3H, t), 1.05 (3H, t); MS(ESI): 544 (MH⁺).

EXAMPLE 100 A. Preparation of4-chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide

To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride(0.92 g, 4.2 mmol) in anhydrous THF (20 mL) added dropwise a solution ofN,N-dimethylethylenediamine (0.44 mL, 4.0 mmol) in THF (20 mL). Afterstirring 30 min combined with a 1:1 mixture of ice and saturated NaHCO₃(50 mL) and then extracted with EtOAc (3×80 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, concentrated andchromatographed (silica gel, MeOH/DCM, 3:22) to yield the title compound(0.40 g, 37%) as a pale yellow solid. ¹H-NMR (CDCl₃): δ 8.28 (1H, d),7.96 (1H, dd), 7.63 (1H, d), 6.98 (1H, br s), 3.54 (2H, m), 2.56 (2H,t), 2.30 (6H, s)

B. Preparation of N-(2-dimethylaminoethyl)-4-ethylamino-3-nitrobenzamide

To 2.0 M solution of ethylamine in THF (8 mL, 16 mmol) slowly added4-chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide (0.40 g, 1.5 mmol).After heating at 65° C. for 16 h, the reaction mixture was cooled,concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to affordthe title compound (0.30 g, 73%) as a yellow solid. ¹H-NMR (CD₃OD): δ8.75 (1H, d), 8.32 (1H, br s), 7.98 (1H, dd), 7.08 (1H, d), 3.58–3.64(3H, m), 3.43–3.51 (2H, m), 2.94 (2H, br t), 2.62 (6H, s), 1.35 (3H, t).

C. Preparation of3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-(2-dimethylaminoethyl)-4-ethylaminobenzamide

In a manner similar to Example 30, intermediateN-(2-dimethylaminoethyl)-4-ethylamino-3-nitrobenzamide was hydrogenatedand then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound.

¹H-NMR (CDCl₃): δ 7.44–7.54 (5H, m), 7.28–7.38 (4H, m), 7.18 (1H, m),7.04 (1H, d), 6.89 (1H, brs), 6.52 (1H, d), 5.19 (2H, s), 3.99 (1H, brt), 3.76 (3H, s), 3.59 (2H, m), 3.02 (2H, m), 2.68 (2H, br s), 2.40 (6H,s), 1.03 (3H, t); MS(ESI): 587 (MH⁺).

EXAMPLE 101 A. Preparation of4-(4,5-dihydrooxazol-2-yl)-N¹-ethylbenzene-1,2-diamine

To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride(1.85 g, 8.4 mmol) in anhydrous THF (60 mL) was added dropwise asolution of ethanolamine (0.48 mL, 8.0 mmol) in THF (20 mL) followed byTEA (1.1 mL, 8.0 mmol). After stirring 1 h while temperature wasmaintained at −10° C., the solution was combined with a 1:1 mixture ofice and saturated NaHCO₃ (100 mL) and then extracted with EtOAc (3×100mL). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (1.74 g, 89%) as a whitesolid, which was used without purification. TLC (3:22 MeOH/DCM R_(f)0.36).

To a solution of intermediate4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (0.40 g, 1.6 mmol) inanhydrous DCM (20 mL) added dropwise thionyl chloride (0.29 mL, 4.0mmol). After stirring 2 h the reaction mixture was diluted withchloroform and concentrated. The resulting yellow oil was dilutedcautiously with 2.0 M solution of ethylamine in THF (10 mL, 20 mmol) andheated in a sealed tube at 65° C. After 2 h the reaction mixture wascooled, concentrated and diluted with THF (20 mL). This solution wascombined with an aqueous solution of 20% KOH (5 mL) andtetrabutylammonium bromide (20 mg). After stirring rapidly 2 h themixture was extracted with Et₂O (2×100 mL). The combined organic layerswere washed with water and brine, dried over MgSO₄, concentrated andchromatographed (silica gel, MeOH/DCM, 1:19) to yield[4-(4,5-dihydrooxazol-2-yl)-2-nitrophenyl]ethylamine (0.17 g, 45%) as ayellow solid. TLC (1:19 MeOH/DCM R_(f) 0.56).

To a solution of this oxazoline intermediate (71 mg, 0.30 mmol) inethanol (2 mL) was added zinc dust (0.20 g) and HOAc (0.20 mL). Observedinitial exotherm and continued stirring 30 min. The reaction mixture wasdiluted with Et₂O (20 mL), filtered, combined cautiously with 15% NH₄OH(10 mL), and extracted again with Et₂O. The organic layers werecombined, washed with brine, dried over Na₂SO₄, and concentrated underreduced pressure to yield the title compound (60 mg, 97%) as anoff-white solid, which was used without purification. ¹H-NMR (CDCl₃): δ7.45 (1H, dd), 7.35 (1H, d), 6.60 (1H, d), 4.38 (2H, t), 4.01 (2H, t),3.69 (1H, br s), 3.26 (2H, br s), 3.21 (2H, m), 1.32 (3H, t); TLC (1:19MeOH/DCM R_(f) 0.12).

B. Preparation of3-benzyl-2-[5-(4,5-dihydrooxazol-2-yl)-2-ethylaminophenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to Example 1 byreplacing aniline with intermediate4-(4,5-dihydrooxazol-2-yl)-N¹-ethylbenzene-1,2-diamine. ¹H-NMR (CDCl₃):δ 7.64 (1H, d), 7.55 (1H, d), 7.52 (1H, d), 7.45–7.49 (2H, m), 7.27–7.37(4H, m), 7.18 (1H, m), 7.04 (1H, d), 6.55 (1H, d), 5.19 (2H, s), 4.38(2H, t), 4.02 (2H, t), 3.77 (3H, s), 3.04 (2H, m), 1.05 (3H, s);MS(ESI): 542 (MH⁺).

EXAMPLE 102 A. Preparation of 1-methyl-2-methylthioquinoliniump-toluenesulfonate

A mixture of 1-methylquinolin-2-thione (175 mg, 1.0 mmol) and methylp-toluenesulfonate (186 mg, 1.0 mmol) was heated at 130° C. After 30 minthe resulting solid was cooled, crushed, triturated with Et₂O (4×1 mL)and dried under high vacuum to give the title compound (0.35 g, 97%) asa white solid. ¹H-NMR (DMSO-d₆): δ 8.96 (1H, d), 8.46 (1H, d), 8.35 (1H,dd), 8.16 (1H, m), 8.08 (1H, d), 7.91 (1H, m), 7.47 (2H, d), 7.10 (2H,d), 4.40 (3H, s), 3.02 (3H, s), 2.28 (3H, s)

B. Preparation of3-[3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

In a manner similar to Example 45, intermediate1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile toafford the title compound. ¹H-NMR (CDCl₃): δ 7.41–7.58 (4H, m),7.20–7.38 (9H, m), 6.49 (1H, d), 5.16 (2H, s), 3.79 (3, brs), 3.01 (2H,q), 1.02 (3H, t); MS(ESI): 492 (MH⁺).

EXAMPLE 103 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)thiazolidin-4-one

In a manner similar to Example 102, 1-methyl-2-methylthioquinoliniump-toluenesulfonate was condensed with2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to affordthe title compound. ¹H-NMR (CDCl₃): δ 7.66–7.71 (2H, m), 7.43–7.56 (4H,m), 7.20–7.38 (7H, m), 6.53 (1H, d), 5.20 (2H, s), 3.78 (3H, br s), 3.07(2H, q), 2.51 (3H, s), 1.06 (3H, t); MS(ESI): 509 (MH⁺).

EXAMPLE 104 Preparation of3-benzyl-2-benzylimino-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with benzylamine. ¹H-NMR (CDCl₃): δ7.46–7.57 (3H, m), 7.22–7.37 (9H, m), 7.15 (1H, m), 7.03 (1H, br d),5.09 (2H, br s), 4.49 (2H, br s), 3.85 (3H, s); MS(ESI): 444 (MH⁺).

EXAMPLE 105 Preparation of2-(3-acetylphenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 79 by replacing 3-picolyl isothiocyanate hydrobromide with2-furfuryl isothiocyanate. MS(ESI): 462 (MH⁺).

EXAMPLE 106 Preparation ofN-{4-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 105 by replacing 3′-aminoacetophenone with 4′-aminoacetanilide.MS(ESI): 477 (MH⁺).

EXAMPLE 107 Preparation of[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-yl]aceticacid methyl ester

The title compound was prepared in a manner similar to Example 1 byreplacing 3-benzylrhodanine with rhodanine-3-acetic acid methyl ester.MS(ESI): 497 (MH⁺).

EXAMPLE 108 A. Preparation of 2-cyano-4-nitroacetanilide

The title compound was prepared in a manner similar to Example 80 byreplacing 2-amino-5-nitropyridine with 5-nitroanthranilonitrile. ¹H-NMR(CDCl₃): δ 8.78 (1H, d), 8.49 (1H, d), 8.44 (1H, dd), 7.88 (1H, br s),2.35 (3H, s).

B. Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide

In a manner similar to Example 30, intermediate2-cyano-4-nitroacetanilide was hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 8.30(1H, d), 7.49–7.57 (4H, m), 7.27–7.38 (5H, m), 7.22 (1H, d), 7.19 (1H,m), 7.07 (1H, d), 5.14 (2H, s), 3.76 (3H, s), 2.27 (3H, s); MS(ESI): 512(MH⁺).

EXAMPLE 109 A. Preparation of 4′-ethoxy-3′-nitroacetophenone

To a solution of 4′-hydroxy-3′-nitroacetophenone (1.0 g, 5.5 mmol) inanhydrous DMF (20 mL) was added anhydrous K₂CO₃ (3.0 g, 22 mmol) andthen bromoethane (0.49 mL, 6.6 mmol). After heating at 80° C. for 20 h,the reaction mixture was cooled, combined with saturated aqueous NH₄Cl(50 mL) and extracted with Et₂O (2×100 mL). The combined organic layerswere washed with water (3×50 mL), 1 N NaOH (50 mL) and then brine (50mL), dried over Na₂SO₄ and concentrated under reduced pressure to affordthe title compound (1.1 g, 96%) as a light brown solid, which was usedwithout further purification. ¹H-NMR (CDCl₃): δ 8.41 (1H, d), 8.15 (1H,dd), 7.14 (1H, d), 4.28 (2H, q), 2.61 (3H, s), 1.52 (3H, t).

B. Preparation of2-(5-acetyl-2-ethoxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

In a manner similar to Example 30, intermediate4′-ethoxy-3′-nitroacetophenone was hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.77(1H, dd), 7.64–7.68 (2H, m), 7.61 (1H, d), 7.48 (1H, m), 7.25–7.36 (4H,m), 7.15 (1H, m), 6.99 (1H, d), 6.98 (1H, d), 5.20 (2H, s), 4.11 (2H,q), 3.69 (3H, s), 2.57 (3H, s), 1.43 (3H, t); MS(ESI): 516 (MH⁺).

EXAMPLE 110 Preparation of2-(5-acetyl-2-hydroxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

In a manner similar to Example 30, 4′-hydroxy-3′-nitroacetophenone washydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 488 (MH⁺).

EXAMPLE 111 A. Preparation of3-benzyl-1-methyl-2-thioxoimidazolidin-4-one

To a solution of sarcosine methyl ester hydrochloride (0.56 g, 4.0 mmol)and DBU (0.60 mL, 4.0 mmol) in anhydrous ethanol added benzylisothiocyanate (0.53 mL, 4.0 mmol). The resulting solution was heated atreflux 16 h, cooled, concentrated and chromatographed (silica gel, DCM)to give the title compound (0.88 g, quant.). ¹H-NMR (CDCl₃): δ 7.49–7.53(2H, m), 7.28–7.35 (3H, m), 5.02 (2H, s), 4.03 (2H, s), 3.34 (3H, s).

B. Preparation of3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-one

To a mixture of intermediate3-benzyl-1-methyl-2-thioxoimidazolidin-4-one (0.33 g, 1.5 mmol) and3-methyl-2-methylthiobenzothiazol-3-ium p-toluenesulfonate 0.66 g, 1.8mmol) in anhydrous MeCN (10 mL) added dropwise TEA (0.28 mL, 2.0 mmol).After 2 h the resulting product mixture was concentrated andchromatographed (silica gel, DCM) to afford the title compound (0.47 g,85%) as an orange-yellow solid. ¹H-NMR (CDCl₃): δ 7.54–7.61 (3H, m),7.46 (1H, m), 7.21–7.33 (5H, m), 5.19 (2H, s), 3.86 (3H, s), 3.77 (3H,s).

C. Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)imidazolidin-4-one

In a manner similar to Example 1, intermediate3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-onewas alkylated with methyl p-toluenesulfonate and condensed with3′-amino-4′-ethylaminoacetophenone to yield the title compound. ¹H-NMR(CDCl₃): δ 8.11 (1H, d), 7.84 (1H, dd), 7.51 (1H, dd), 7.31 (1H, m),7.16 (1H, m), 6.95–7.12 (7H, m), 6.08 (1H, br t), 4.46 (2H, hs m), 3.99(2H, m), 3.78 (3H, s), 3.50 (3H, s), 2.65 (3H, s), 1.06 (3H, t);MS(ESI): 512 (MH⁺).

EXAMPLE 112 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(2-morpholin-4-ylethyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide withN-(2-ethylisothiocyanate)morpholine, synthesized fromN-(2-aminoethyl)morpholine and thiophosgene. ¹H-NMR (CDCl₃): δ 7.52 (1H,d), 7.32–7.37 (2H, m), 7.18–7.23 (2H, m), 7.09 (1H, d), 6.60 (¹H, d),4.75 (1H, br s), 4.16 (1H, t), 3.81 (3H, s), 3.71 (4H, br s), 3.23 (2H,q), 2.76 (2H, br s), 2.60 (4H, br s), 1.29 (3H, t); MS(ESI): 521 (MH⁺).

EXAMPLE 113 Preparation of4-ethylamino-3-[3-(4-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with4-methoxybenzylisothiocyanate. MS(ESI): 528 (MH⁺).

EXAMPLE 114 Preparation of4-ethylamino-3-[3-(3-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-methoxybenzylisothiocyanate. ¹H-NMR (CDCl₃): δ 7.55 (1H, d), 7.37 (1H,t), 7.22–7.32 (4H, m), 7.12 (1H, d), 7.01 (2H, m), 6.86 (1H, d), 6.51(1H, d), 5.16 (2H, s), 4.32 (1H, t), 3.84 (3H, s), 3.81 (3H, s), 3.03(2H, q), 1.05 (3H, t); MS(ESI): 528 (MH⁺). Recrystallization of theproduct from hot MeCN afforded crystals suitable for single-crystalX-ray diffraction. Structural analysis showed that the E-isomer had beenobtained.

EXAMPLE 115 Preparation of4-ethylamino-3-[3-(2-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with2-methoxybenzylisothiocyanate. MS(ESI): 528 (MH⁺).

EXAMPLE 116 A. Preparation of2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1,3-phenylenediamine. MS(ESI): 445(MH⁺).

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}succinamicacid

To a 25 mL flask was added2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one(100 mg, 225 μmol), anhydrous DCM (5 mL) and CHCl₃ (3 mL). To thesolution was added succinic anhydride (23 mg, 239 μmol). The reactionsolution was allowed to stir at 50° C. for 1.5 h. The white precipitateswere collected by filtration under reduced pressure, washed with DCM (10mL) and hexanes (20 mL), and then dried under vacuum to give the titlecompound (75 mg, 61%). MS(ESI): 545 (MH⁺).

EXAMPLE 117 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}benzenesulfonamide

To a 25 mL flask was added2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one(0.18 g, 0.40 mmol), anhydrous CHCl₃ (7 mL), benzenesulfonyl chloride(56 μL, 0.44 mmol), and TEA (0.10 mL, 0.80 mmol). The solution wasstirred at 50° C. for 20 h. The yellow precipitates were collected byfiltration under reduced pressure, washed with hexanes (30 mL), anddried under vacuum to give the title compound (49 mg, 21%) as a yellowsolid. ¹H-NMR (DMSO-d₆): δ 7.97 (1H, s), 7.76 (2H, d), 7.53 (2H, m),7.45 (2H, t), 7.37 (2H, d), 7.09–7.31 (8H, m), 6.81 (1H, d), 6.74 (1H,s), 6.57 (1H, d), 4.99 (2H, s), 3.72 (3H, s); MS(ESI): 585 (MH⁺).

EXAMPLE 118 Preparation of thiophen-2-sulfonic acid{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}amide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride with2-(thiophene)sulfonyl chloride. MS(ESI): 591 (MH⁺).

EXAMPLE 119 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-3-methoxybenzamide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride with 3-methoxybenzoylchloride. MS(ESI): 579(MH⁺).

EXAMPLE 120 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride with methanesulfonylchoride. ¹H-NMR (CDCl₃): δ 8.88 (1H, s), 7.48 (2H, d), 7.41 (1H, d),7.16–7.26 (5H, m), 7.09 (1H, t), 6.96 (2H, t), 6.89 (1H, m), 6.70 (1H,d), 5.05 (2H, s), 3.67 (3H, s), 2.92 (3H, s); MS(ESI): 532 (MH⁺).

EXAMPLE 121 Preparation of{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamicacid ethyl ester

The title compound was prepared in a manner similar to the described inExample 117 by replacing benzenesulfonyl chloride with ethylchloroformate. MS(ESI): 517 (MH⁺).

EXAMPLE 122 Preparation of3-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-1,1-dimethylurea

The title compound was prepared in a manner similar to the described inExample 117 by replacing benzenesulfonyl chloride with dimethylcarbamylchloride. MS(ESI): 523(MH⁺).

EXAMPLE 123 A. Preparation of morpholin-4-ylacetyl chloridehydrochloride

To a 100 mL flask was added morpholine (5.5 g, 63 mmol), benzene (20mL), and ethyl chloroacetate (3.2 mL, 30 mmol). The reaction solutionwas allowed to stir 1 h at ambient temperature. The resulting whitecrystalline solids were collected by filtration under reduced pressureand then transferred to a 100 mL flask along with dioxane (20 mL) and 1NNaOH (33 mL). The solution was allowed to stir at 80° C. for 16 h,cooled and then neutralized with 1N HCl. The aqueous solution was frozenand lyophilized to isolate the crude morpholinylacetic acid. The crudeacid (2.6 g, 20 mmol) and thionyl chloride (15 mL) was added to aN₂-purged 100 mL flask. After stirring 3 h the reaction solution wasfiltered and concentrated under reduced pressure to provide the titlecompound (3.1 g, 78%) as a white powder. ¹H-NMR (DMSO-d₆): δ 7.58 (1H,s), 3.48 (2H, s), 3.37 (4H, m), 2.76 (4H, m); ¹³C-NMR (DMSO-d₆): δ166.0, 63.5, 55.5, 51.8.

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride withmorpholin-4-ylacetyl chloride hydrochloride. ¹H-NMR (CDCl₃): δ 8.98 (1H,s), 7.51 (2H, d), 7.41 (1H, d), 7.34 (1H, d), 7.19–7.27 (5H, m), 7.08(2H, m), 6.91 (1H, d), 6.70 (1H, d), 5.06 (2H, s), 3.70 (4H, t), 3.63(3H, s), 3.07 (2H, s), 2.55 (4H, t); MS(ESI): 572 (MH⁺).

EXAMPLE 124 Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 123. MS(ESI): 572 (MH⁺).

EXAMPLE 125 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide

To a 25 mL flask was added N,N-dimethylglycine (500 mg, 4.85 mmol) andthionyl chloride (5 mL). The resulting solution was allowed to stir atambient temperature under N₂ for 3 h. The excess thionyl chloride wasremoved in vacuo to provide N,N-dimethylaminoacetyl chloridehydrochloride as a white powder.

To a solution of2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one(160 mg, 360 μmol) in chloroform (8 mL) was addedN,N-dimethylaminoacetyl chloride hydrochloride (90 mg, 0.58 mmol) andTEA (150 μL, 1.1 mmol). The reaction solution was heated at reflux for20 h, cooled, and concentrated in vacuo. The crude material waschromatographed (silica gel, 0–50% EtOAc/Hex) to give the title compound(34 mg, 18%) as a yellow solid. ¹H-NMR (CDCl₃): δ 9.03 (1H, s), 7.50(2H, d), 7.37 (2H, t), 7.17–7.26 (5H, m), 7.11 (1H, m), 7.05 (1H, t),6.88 (1H, d), 6.68 (1H, d), 5.03 (2H), 3.60 (3H, s), 3.00 (2H, s), 2.28(6H, s); MS(ESI): 530(MH⁺).

EXAMPLE 126 Preparation of{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamicacid ethyl ester

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 121. ¹H-NMR (CDCl₃): δ 7.49(2H, d), 7.37 (1H, d), 7.20–7.29 (5H, m), 7.07 (1H, t), 6.87–6.95 (3H,m), 6.54 (1H, br s), 5.07 (2H, s), 4.15 (2H, q), 3.61 (3H, s), 1.24 (3H,t); MS(ESI): 517(MH⁺).

EXAMPLE 127 Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 125. MS(ESI) 530(MH⁺).

EXAMPLE 128 Preparation ofN-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 120. MS(ESI): 523 (MH⁺).

EXAMPLE 129 Preparation of4-ethylamino-3-[3-(3-hydroxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

To a N₂-purged flask was added the product of Example 114 (60 mg, 0.11mmol) and anhydrous DCM (5 mL). The solution was cooled to −78° C. priorto the addition of a 1.0M solution of BBr₃ in DCM (0.50 mL). Thesolution was allowed to warm to ambient temperature with stirring. After7 h the solution was quenched by addition of MeOH (10 mL) and thenconcentrated under reduced pressure. The crude material was purified byreverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H₂O (1:9to 9:1) to provide the title compound (15 mg, 26%). ¹H-NMR (CDCl₃): δ7.40 (1H, d), 7.35 (1H, t), 7.29 (1H, dd), 7.13–7.25 (3H, m), 6.95–7.01(3H, m), 6.76 (1H, dd), 6.49 (1H, d), 5.08 (2H, s), 3.56 (3H, s), 3.02(2H, q), 1.05 (3H, t); MS(ESI): 514(MH⁺).

EXAMPLE 130 Preparation of 4′-ethylamino-3′-nitroacetanilide

To a solution of 4-fluoro-3-nitroaniline (2.5 g, 16 mmol) in DCM (35 mL)was added acetic anhydride (2.3 mL, 24 mmol). The solution was stirred15 min, and the resulting off-white precipitates were collected byfiltration under reduced pressure. To a solution of the intermediateacetanilide in anhydrous THF (15 mL) was added a 2.0M solution ofethylamine in THF (8.0 mL). The solution was stirred at ambienttemperature 14 h, and the resulting precipitates were collected byfiltration under reduced pressure and dried under vacuum to provide thetitle compound (2.4 g, 68%). ¹H-NMR (CDCl₃): δ 8.08 (1H, d), 7.90 (1H,br s), 7.78 (1H, dd), 7.32 (1H, br s), 6.82 (1H, d), 3.35 (2H, q), 2.16(3H, s), 1.36 (3H, t).

B. Preparation of4-ethylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]acetanilide

In a manner similar to Example 30, intermediate4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensedwith3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 9.58(1H, s), 7.76 (1H, d), 7.18–7.46 (9H, m), 7.12 (1H, d), 6.47 (1H, d),5.09 (2H, s), 3.82 (1H, br s), 3.79 (3H, s), 2.92 (2H, t), 1.98 (3H, s),0.97 (3H, t); MS(ESI): 530(MH⁺).

EXAMPLE 131 Preparation of4-ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was synthesized in a manner similar or to thatdescribed in Example 83 by replacing 3-picolyl isothiocyanatehydrobromide with 3-fluorobenzylisothiocyanate. MS(ESI): 516 (MH⁺).

EXAMPLE 132 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(3-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-(trifluoromethyl)benzylisothiocyanate. MS(ESI): 566 (MH⁺).

EXAMPLE 133 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(2-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with2-(trifluoromethyl)benzylisothiocyanate. MS(ESI): 566 (MH⁺).

EXAMPLE 134 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(3-methylbenzyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-methylbenzylisothiocyanate. MS(ESI): 512(MH⁺).

EXAMPLE 135 A. Preparation of4′-ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilid

The title compound was synthesized in a manner similar to Example 130 byreplacing acetic anhydride with morpholin-4-ylacetyl chloridehydrochloride. ¹H-NMR (CDCl₃): δ 8.94 (1H, s), 8.11 (1H, d), 7.88 (1H,dd), 6.83 (1H, d), 3.78 (4H, t), 3.34 (2H, q), 3.13 (2H, s), 2.62 (4H,t), 1.31 (3H, t).

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-morpholin-4-ylacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilide was hydrogenatedand then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDC₃): δ 8.87(1H, s), 7.49–7.53 (3H, m), 7.28–7.37 (5H, m), 7.19 (1H, t), 7.12 (1H,dd), 7.04 (1H, d), 6.57 (1H, d), 5.19 (2H, s), 3.79 (8H, br s), 3.16(2H, s), 3.01 (2H, q), 2.66 (4H, br s), 1.06 (3H, t); MS(ESI): 615(MH⁺).

EXAMPLE 136 Preparation of3-[3-(3-chlorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-chlorobenzylisothiocyanate. MS(ESI): 533 (MH⁺).

EXAMPLE 137 Preparation of3-[3-(3-bromobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-bromobenzylisothiocyanate. MS(ESI): 578(MH⁺).

EXAMPLE 138 A. Preparation of4′-ethylamino-3′-nitro-2,2,2-trifluoroacetanilide

The title compound was prepared in a manner similar to that described inExample 130 by replacing acetic anhydride with trifluoroacetic anhydride(TFAA). TLC (1:1 Hex/EtOAc) R_(f)=0.5; MS(ESI): 278(MH⁺).

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2,2,2-trifluoroacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-3′-nitro-2,2,2-trifluoroacetanilide was hydrogenated andthen condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 584(MH⁺).

EXAMPLE 139 A. Preparation of2-dimethylamino-4′-ethylamino-3′-nitroacetanilide

The title compound was prepared in a similar manner as that described inExample 130 by replacing acetic anhydride with N,N-dimethylaminoacetylchloride hydrochloride. ¹H-NMR (CDCl₃): δ 9.04 (1H, s), 8.16 (1H, d),7.95 (1H, dd), 7.89 (1H, br s), 6.84 (1H, d), 3.35 (2H, q), 3.09 (2H,s), 2.39 (6H, s), 1.36 (3H, t); MS(ESI): 267(MH⁺).

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide

In a manner similar to Example 30, intermediate2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated andthen condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 8.85(1H, s), 7.43 (3H, t), 7.18–7.28 (5H, m), 7.10 (2H, t), 6.95 (1H, d),6.48 (1H, d), 5.10 (2H, s), 3.71 (3H, s), 3.03 (2H, s), 2.93 (2H, q),2.33 (6H, s), 0.97 (3H, t); MS(ESI): 584(MH⁺).

EXAMPLE 140 A. Preparation of 4-ethylamino-3-nitroaniline

To a pressure tube was added 4-fluoro-3-nitroaniline (550 mg, 3.50 mmol)and a 2.0 M solution of ethylamine in THF (8 mL). The sealed tube washeated at 120° C. for 24 h. The reaction solution was cooled, dilutedwith EtOAc (30 mL), washed with saturated NaHCO₃ (2×25 mL), dried overNa₂SO₄, and concentrated under reduced pressure to provide the titlecompound (625 mg, 98%) as a purple solid. ¹H-NMR (CDCl₃): δ 7.72 (1H, brs), 7.49 (1H, d), 6.96 (1H, dd), 6.74 (1H, d), 3.45 (2H, br s), 3.30(2H, m), 1.33 (3H, t).

B. Preparation of 4-methylpiperazine-1-carboxylic acid(4-ethylamino-3-nitro-phenyl)amide

To a 100 mL flask was added 4-ethylamino-3-nitroaniline (625 mg, 3.45mmol), chloroform (30 mL), and triphosgene (341 mg, 1.15 mmol). To thesolution was added saturated NaHCO₃ (30 mL), and the biphasic mixturewas stirred for 30 min. The organic phase was partitioned, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas dissolved in anhydrous THF (16 mL), and 4-methylpiperizine (291 mg,2.90 mmol) was added. The solution was stirred at 40° C. for 1 h, cooledand concentrated under reduced pressure to provide the title compound(1.0 g, 94%) as a red solid. ¹H-NMR (CDCl₃): δ 7.91 (1H, d), 7.84 (1H,t), 7.61 (1H, dd), 6.95 (1H, s), 6.73 (1H, d) 3.52 (4H, t), 3.31 (2H,m), 2.42 (4H, t), 2.32 (3H, s), 1.34 (3H, t); MS(ESI): 308(MH⁺).

C. Preparation of 4-methylpiperazine-1-carboxylic acid{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}amide

In a manner similar to Example 30, intermediate4-methylpiperazine-1-carboxylic acid (4-ethylamino-3-nitro-phenyl)amidewas hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 614(MH⁺).

EXAMPLE 141 Preparation of2-(5-amino-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

To the product of Example 138 (0.15 g, 0.26 mmol) in MeOH (30 mL) wasadded H₂O (6 mL) and fine mesh K₂CO₃ (0.30 g, 1.5 mmol), and thesolution was stirred 24 h at 55° C. The reaction mixture was cooled,diluted with EtOAc (30 mL), washed with H₂O (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFAin MeCN—H₂O (1:9 to 9:1) to provide the title compound (2 mg). MS(ESI):488(MH⁺).

EXAMPLE 142 A. Preparation of4′-ethylamino-2-(4-methylpiperazin-1-yl)-3′-nitroacetanilide

To a 100 mL flask was added 4-fluoro-3-nitroaniline (0.83 g, 5.3 mmol),DCM (30 mL), bromoacetyl chloride (0.53 mL, 6.4 mmol), and TEA (0.74 mL,5.3 mmol). The reaction solution was stirred at room temperature 2 h andthen quenched with saturated NaHCO₃ (20 mL). The organic phase waspartitioned, dried over Na₂SO₄, filtered under vacuum, and concentratedunder reduced pressure. The resulting amide (1.31 g, 4.73 mmol) wasadded to a 100 mL flask along with MeCN (20 mL), 4-methylpiperizine(0.53 mL, 4.7 mmol), and K₂CO₃ (655 mg, 4.74 mmol). The reaction slurrywas stirred 14 h at 35° C. prior to removal of excess K₂CO₃ by vacuumfiltration. The filtrate was concentrated under reduced pressure, andthe crude residue was chromatographed (SiO₂, hexane/EtOAc) to provide400 mg of intermediate amide. In a manner similar to that described inExample 31, the intermediate amide was treated with ethylamine to affordthe title compound. ¹H-NMR (CDCl₃): δ 9.66 (1H, s), 8.44 (1H, m), 8.05(1H, m), 7.17 (1H, t), 3.25 (2H, s), 3.19 (4H, m), 3.14 (2H, m), 2.88(4H, m), 2.53 (3H, 2), 1.38 (3H, t); MS(ESI): 322(MH⁺).

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-(4-methylpiperazin-1-yl)acetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-(4-methylpiperazin-1-yl)-3′-nitroacetanilide washydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluene sulfonate to afford the title compound. MS(ESI): 628(MH⁺).

EXAMPLE 143 Preparation ofN-{3-[3-benzyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide

The title compound was prepared in a manner similar to Example 1 byreplacing 2-(methylthio)benzothiazole with2-mercapto-5-methoxybenzothiazole and by replacing aniline with3′-amino-2-dimethylamino-4′-ethylaminoacetanilide. MS(ESI): 603(MH⁺).

EXAMPLE 144 Preparation ofN-{3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide

The title compound was prepared from the product of Example 143 in amanner similar to that described in Example 129. MS(ESI): 589 (MH⁺).

EXAMPLE 145 A. Preparation of5-(2-chloroethoxy)-2-methylthio-benzothiazole

To a 250 mL flask was added 2-mercapto-5-methoxybenzothiazole (5.1 g, 26mmol), MeCN (63 mL), methyl p-toluenesulfonate (4.8 g, 26 mmol) and TEA(4.4 mL, 31 mmol). After stirring 16 h at ambient temperature, thesolution was concentrated under reduced pressure. The crude material wasdiluted with EtOAc (200 mL), washed with water (2×75 mL), dried overNa₂SO₄, filtered, and concentrated. The resulting viscous oil wasdissolved in DCM (40 mL), and transferred to an argon-purged 250 mLflask. The solution was cooled to −78° C. prior to the addition of a 1.0M BBr₃ solution in DCM (64 mL). The reaction suspension was allowed towarm to room temperature. After 16 h the reaction solution was cooled to−78° C. and quenched by addition of MeOH (100 mL). The resultingprecipitates were isolated by vacuum filtration to yield5-hydroxy-2-methylthio-benzothiazole (3.9 g, 76%) as a white solid.

To a solution of 5-hydroxy-2-methylthio-benzothiazole (2.1 g, 11 mmol)in anhydrous DMF (25 mL) was added bromo-2-chloroethane (4.4 mL, 53mmol) and powdered K₂CO₃ (7.3 g, 53 mmol). The reaction slurry washeated at 70° C. for 13 h. The slurry was filtered under vacuum and thefiltrate was concentrated under reduced pressure. The crude material waschromatographed (SiO₂, 0–20% EtOAc/Hex) to afford the title compound(1.2 g, 46%). ¹H-NMR (CDCl₃): δ 7.62 (1H, d), 7.39 (1H, d), 6.97 (1H,dd), 4.29 (2H, t), 3.85 (2H, t), 2.79 (3H, s); MS(ESI): 259(MH⁺).

B. Preparation of3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-(methylthio)benzothiazole with5-(2-chloroethoxy)-2-methylthio-benzothiazole. ¹H-NMR (DMSO-d₆): δ 8.08(1H, d), 7.65 (1H, d), 7.36–7.53 (7H, m), 7.22 (1H, dd), 7.09 (1H, d),5.38 (2H, s), 4.45 (2H, t), 4.25 (3H, s), 4.03 (2H, t), 3.01 (3H, s),2.28 (3H, s) MS(ESI): 463 (M⁺—p-toluenesulfonate).

C. Preparation ofN-(3-{3-benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

In a manner similar to Example 30, intermediate2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated andthen condensed with3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 651 (MH⁺).

EXAMPLE 146 A. Preparation of3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate

The title compound was synthesized in a manner similar to that describedin Example 145 by replacing bromo-2-chloroethane with 2-chloroethylmethylether. MS(ESI): 459 (M⁺—p-toluenesulfonate).

B. Preparation ofN-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

In a manner similar to Example 30, intermediate2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated andthen condensed with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 9.08(1H, s), 7.46 (2H, d), 7.27–7.35 (5H, m), 7.16 (1H, dd), 6.69 (1H, dd),6.62 (1H, d), 6.51 (1H, d), 5.14 (2H, s), 4.13 (2H, t), 3.75 (2H, t),3.71 (2H, s), 3.44 (3H, s), 3.19 (2H, s), 2.94 (2H, q), 2.46 (6H, s),1.02 (3H, t); MS(ESI): 647(MH⁺).

EXAMPLE 147 A. Preparation of4′-ethylamino-2-methoxy-3′-nitroacetanilide

The title compound was prepared in a similar manner as that described inExample 130 by replacing acetic anhydride with methoxyacetyl chloride.

¹H-NMR (CDCl₃): δ 8.20 (1H, d), 8.17 (1H, br s), 7.88 (1H, dd), 6.68(1H, d), 4.03 (2H, s), 3.52 (3H, s), 3.37 (2H, q), 1.62 (2H, br s), 1.38(3H, t).

B. Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-methoxyacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.99(1H, s), 7.39–7.44 (3H, m), 7.17–7.28 (5H, m), 7.05–7.11 (2H, m), 6.94(1H, d), 6.50 (1H, d), 5.08 (2H, s), 3.92 (2H, s), 3.66 (3H, s), 3.41(3H, s), 2.91 (2H, q), 0.96 (3H, t); MS(ESI): 560(MH⁺).

EXAMPLE 148 Preparation ofN-(3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

To a pressure tube was added the product of Example 145 (150 mg, 0.23mmol), tetra-n-butylammonium iodide (85 mg, 0.23 mmol), and 2.0 Msolution of dimethylamine in THF (6 mL). The tube was sealed and heatedat 65° C. for 14 h. The solution was cooled and concentrated underreduced pressure, and the crude material was purified by chromatography(silica gel, 0–20% MeOH/DCM) to provide the title compound (30 mg, 20%).¹H-NMR (CDCl₃): δ 8.83 (1H, s), 7.45 (2H, d), 7.22–7.34 (5H, m), 7.11(1H, dd), 6.71 (1H, dd), 6.63 (1H, d), 6.52 (1H, d), 5.14 (2H, s), 4.12(2H, t), 3.70 (3H, s), 3.04 (2H, s), 2.97 (2H, q), 2.82 (2H, t), 2.40(6H, s), 2.35 (6H, s), 1.02 (3H, t); MS(ESI): 660(MH⁺).

EXAMPLE 149 Preparation ofN-(3-{3-benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylamino-acetamide

To an 8 mL vial was added the product of Example 145 (100 mg, 0.15mmol), anhydrous DMF (5 mL), and tetra-n-butylammonium iodide (570 mg,1.54 mmol). The solution was heated at 75° C. for 4 h prior to theaddition of sodium acetate (250 mg, 3.08 mmol). The reaction solutionwas then heated 16 h at 75° C. To the solution was added MeOH (2 mL), 5Maqueous NaOH (1 mL) and H₂O (1 mL). After heating at 50° C. for 5 h, thereaction mixture was cooled, neutralized with conc HCl and concentratedunder reduced pressure. The residue was taken up into DCM (50 mL), andthe organic phase was washed with water (2×25 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas chromatographed (SiO₂, 0–10% MeOH/DCM) to provide the title compound(5 mg, 5%). ¹H NMR (MeOH-d₄): δ 8.92 (1H, s), 7.11–7.26 (7H, m), 6.97(1H, dd), 6.66 (1H, dd), 6.60 (1H, d), 6.44 (1H, d), 5.01 (2H, s), 3.96(2H, t), 3.77 (2H, t), 3.62 (3H, s), 3.00 (2H, s), 2.82 (2H, q), 2.28(6H, s), 0.89 (3H, t); MS(ESI) 633(MH⁺).

EXAMPLE 150 A. Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-thiazolidin-4-one

The title compound was prepared from furfuryl isothiocyanate and3′-amino-4′-(ethylamino)acetophenone in a manner similar to thatdescribed in Example 52. ¹H-NMR (CDCl₃): δ 7.73 (1H, dd), 7.61 (1H, s),7.38 (1H, s), 6.59 (1H, d), 6.43 (1H, d), 6.36 (1H, m), 5.06 (2H, s),3.88 (2H, s), 3.21 (2H, q), 2.50 (3H, s), 1.27 (3H, t); MS(ESI): 358(MH⁺).

B. Preparation of2-(5-acetyl-2-ethylaminophenylimino)-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one

In a manner similar to Example 45, intermediate5-(2-chloroethoxy)-2-(methylthio)benzothiazole was alkylated with methylp-toluenesulfonate and then condensed with the above2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-thiazolidin-4-one.MS(ESI): 583 (MH⁺).

EXAMPLE 151 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was synthesized in a manner similar to that describedin Example 82 by replacing 3-picolyl isothiocyanate hydrobromide with2-furfuryl isothiocyanate. ¹H-NMR (CDCl₃): δ 7.70–7.74 (2H, m), 7.52(1H, d), 7.33–7.39 (2H, m), 7.20 (1H, t), 7.06 (1H, d), 6.68 (1H, d),6.50 (1H, d), 6.35 (1H, m), 5.24 (2H, s), 3.76 (3H, s), 3.23 (2H, q),2.49 (3H, s), 1.28 (3H, t); MS(ESI): 505 (MH⁺).

EXAMPLE 152 Preparation ofN-(3-{3-benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 638(MH⁺).

EXAMPLE 153 Preparation ofN-{4-ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-methoxyacetamide

The title compound was prepared in a manner similar to that described inExample 84 by replacing 3-amino-4-(ethylamino)benzonitrile with3′-amino-4′-ethylamino-2-methoxyacetanilide. ¹H-NMR (CDCl₃): δ 8.07 (1H,s), 7.50 (1H, dd), 7.37 (1H, d), 7.29–7.34 (2H, m), 7.16 (2H, m), 7.02(1H, d), 6.66 (1H, br s), 6.45 (1H, d), 6.32 (1H, m), 5.15 (2H, s), 3.99(2H, s), 3.75 (3H, s), 3.51 (3H, s), 3.13 (2H, q), 1.23 (3H, t);MS(ESI): 550 (MH⁺).

EXAMPLE 154 Preparation ofN-(3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

The title compound was prepared from the product of Example 152 in amanner similar to that described in Example 148. ¹H-NMR (CDCl₃): δ 8.03(1H, s), 7.48 (2H, d), 7.24–7.37 (5H, m), 7.14 (1H, dd), 6.74 (1H, dd),6.65 (1H, d), 6.53 (1H, d), 5.16 (2H, s), 4.13 (2H, t), 4.00 (2H, s),3.72 (3H, s), 3.48 (3H, s), 2.99 (2H, q), 2.81 (2H, t), 2.39 (6H, s),1.03 (3H, t); MS(ESI): 647(MH⁺).

EXAMPLE 155 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-5-[5-(2-dimethylamino-ethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one

The title compound was prepared from the product of Example 150 in amanner similar to that described in Example 148. ¹H-NMR (CDCl₃): δ7.67–7.72 (2H, m), 7.37 (1H, s), 7.35 (1H, d), 6.76 (1H, dd), 6.64 (1H,d), 6.57 (1H, d), 6.45 (1H, d), 6.34 (1H, dd), 5.18 (2H, s), 4.89 (1H,t), 4.10 (2H, t), 3.71 (3H, s), 3.22 (2H, m), 2.75 (2H, m), 2.51 (3H,s), 2.35 (6H, s), 0.97 (3H, t); MS(ESI): 592(MH⁺).

EXAMPLE 156 A. Preparation ofN-[4-ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide

The title compound was synthesized from 2-furfuryl isothiocyanate and3′-amino-4′-ethylamino-2-methoxyacetanilide in a manner similar to thatdescribed in Example 52. MS(ESI): 403 (MH⁺).

B. Preparation ofN-(3-{5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

In a manner similar to Example 45, intermediate5-(2-chloroethoxy)-2-(methylthio)benzothiazole was alkylated with methylp-toluenesulfonate and then condensed with the aboveN-[4-ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide.The resulting product was transformed into the title compound followingthe procedure outlined in Example 148. MS(ESI): 583 (MH⁺).

EXAMPLE 157 A. Preparation of2-acetoxy-4′-ethylamino-3′-nitroacetanilide

To a 100 mL flask was added 4-ethylamino-3-nitroaniline (1.1 g, 6.3mmol) and anhydrous CHCl₃ (45 mL). The solution was cooled to 0° C.prior to the addition of bromoacetyl chloride (0.62 mL, 7.5 mmol) andTEA (1.7 mL, 13 mmol) under a nitrogen atmosphere. The reaction mixturewas allowed to warm to ambient temperature over 1 h before the solventwas removed under reduced pressure. The crude material waschromatographed (SiO₂, 0–40% EtOAc/Hex) to provide the intermediateacetanilide (540 mg, 1.8 mmol) as a red solid. To a solution of theintermediate in anhydrous DMF (25 mL) was added sodium acetate (1.41 g,17.2 mmol). The suspension was heated at 100° C. for 4 h. After cooling,the reaction mixture was diluted with EtOAc (25 mL), and the excesssodium acetate was removed by filtration under reduced pressure. Thefiltrate was concentrated under reduced pressure to provide the titlecompound (420 mg). ¹H-NMR (CDCl₃): δ 8.13 (1H, br s), 8.11 (1H, d), 7.90(1H, br s), 7.79 (1H, dd), 6.80 (1H, d), 4.68 (2H, s), 3.33 (2H, m),2.21 (3H, s), 1.35 (3H, t); MS(ESI): 282 (MH⁺).

B. Preparation of acetic acid{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenylcarbamoyl}methylester

In a manner similar to Example 30, intermediate2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.73(1H, br s), 7.44–7.51 (3H, m), 7.23–7.34 (5H, m), 7.16 (1H, t), 7.08(1H, dd), 7.00 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.67 (2H, s), 3.74(3H, s), 2.98 (2H, q), 2.20 (3H, s), 1.00 (3H, t); MS(ESI): 588(MH⁺).

EXAMPLE 158 Preparation ofN-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-hydroxyacetamide

To a 50 mL flask was added the product of Example 157 (0.19 g, 0.32mmol), CHCl₃ (5 mL), MeOH (10 mL), water (2 mL), and potassium carbonate(0.22 g, 1.6 mmol). After 4 h the reaction mixture was diluted withCHCl₃ (40 mL), and the organic phase was partitioned, washed with water(20 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude sample was chromatographed (silica gel, 0–10%MeOH/DCM) to afford the title compound (37 mg, 21%). ¹H-NMR (CDCl₃): δ8.14 (1H, s), 7.42–7.48 (3H, m), 7.27–7.33 (5H, m), 7.15 (1H, t), 7.09(1H, dd), 6.99 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.14 (2H, s), 3.71(3H, s), 2.95 (2H, q), 0.99 (3H, t); MS(ESI): 546(MH⁺).

EXAMPLE 159 Preparation ofN-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-hydroxyacetamide

In a manner similar to Example 30, intermediate2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford an intermediate thiazolidinone, which washydrolyzed in a manner similar to Example 158 to provide the titlecompound. MS(ESI): 620(MH⁺).

EXAMPLE 160 Preparation of2-(3-acetylphenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one

The title compound was synthesized in a manner similar to that describedin Example 146 by condensing 3′-aminoacetophenone with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate. ¹H-NMR (CDCl₃): δ 7.75 (1H, d), 7.60–7.64 (3H, m),7.28–7.50 (6H, m), 7.24 (1H, d), 6.85 (1H, m), 5.21 (2H, s), 4.18 (2H,m), 3.80 (2H, m), 3.70 (3H, s), 3.48 (3H, s), 2.65 (3H, s); MS(ESI):546(MH⁺).

EXAMPLE 161 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 150 by replacing 5-(2-chloroethoxy)-2-(methylthio)benzothiazolewith 5-(2-methoxyethoxy)-2-(methylthio)benzothiazole. ¹H-NMR (CDCl₃): δ7.69 (1H, dd), 7.66 (1H, d), 7.34–7.37 (2H, m), 6.76 (1H, dd), 6.65 (1H,d), 6.59 (1H, d), 6.45 (1H, d), 6.33 (1H, m), 5.18 (2H, s), 4.14 (2H,m), 3.75 (2H, m), 3.70 (3H, s), 3.44 (3H, s), 3.20 (2H, q), 2.51 (3H,s), 1.26 (3H, t); MS(ESI): 579(MH⁺).

EXAMPLE 162 Preparation ofN-(4-ethylamino-3-{3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}phenyl)-2-methoxyacetamide

In a manner similar to Example 156,5-(2-methoxyethoxy)-2-(methylthio)benzothiazole was alkylated withmethyl p-toluenesulfonate and then condensed with intermediateN-[4-ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide.¹H-NMR (CDCl₃): δ 8.09 (1H, s), 7.28–7.38 (3H, m), 7.15 (1H, dd), 6.76(1H, dd), 6.64 (1H, d), 6.44 (1H, d), 6.33 (1H, m), 5.16 (2H, s), 4.14(2H, m), 4.01 (2H, s), 3.77 (2H, m), 3.72 (3H, s), 3.51 (3H, s), 3.44(3H, s), 3.15 (2H, q), 1.23 (3H, t); MS(ESI): 624(MH⁺).

EXAMPLE 163 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one

The title compound was synthesized in a manner similar to that describedin Example 146 by condensing 3′-amino-4′-(ethylamino)acetophenone with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate. MS(ESI): 546(MH⁺).

EXAMPLE 164 Preparation ofN-(3{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

The title compound was synthesized in a manner similar to that describedin Example 146 by replacing2-dimethylamino-4′-ethylamino-3′-nitroacetanilide with4′-ethylamino-2-methoxy-3′-nitroacetanilide. MS(ESI): 634(MH⁺).

EXAMPLE 165 A. Preparation ofN-(3-{5-[5-(2-azidoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

To a 50 mL flask was added the product of Example 145 (225 mg, 345μmol), anhydrous DMF (8 mL), sodium azide (112 mg, 1.73 mmol), andsodium iodide (15 mg, 103 μmol). The reaction slurry was heated at 70°C. for 6 h under N₂. The reaction mixture was diluted with EtOAc (70mL), washed with H₂O (2×30 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide the title compound.MS(ESI): 658(MH⁺).

B. Preparation ofN-(3-{5-[5-(2-aminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

To a solution of the aboveN-(3-{5-[5-(2-azidoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide(0.34 mmol) in THF (13 mL) was added triphenylphosphine (100 mg, 380mmol) and H₂O (20 mL). The solution was stirred 48 h at roomtemperature. The solvent was removed under reduced pressure, and thecrude material was chromatographed (silica gel, 0–5% MeOH/DCM) to affordthe title compound (157 mg, 72% overall).

¹H-NMR (CDCl₃): δ 8.85 (1H, s), 7.48 (2H, d), 7.27–7.37 (5H, m), 7.13(1H, dd), 6.74 (1H, dd), 6.60 (1H, d), 6.55 (1H, d), 5.17 (2H, s), 4.03(2H, t), 3.73 (3H, s), 3.11 (2H, t), 3.06 (2H, s), 3.00 (2H, q), 2.37(6H, s), 1.39 (2H, t), 1.04 (3H, t); MS(ESI): 631 (MH⁺).

EXAMPLE 166 A. Preparation of 2-dimethylamino-3′-nitroacetanilide

The title compound was prepared from 3-nitroaniline in a manner similarto that described in Example 139. ¹H-NMR (CDCl₃): δ 9.04 (1H, br s),8.39 (1H, t), 8.06 (1H, dd), 7.96 (1H, dd), 7.50 (1H, t), 3.13 (2H, s),2.41 (6H, s).

B. Prepration of2-dimethylamino-N-[3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]acetamide

In a manner similar to that described in Example 52, the title compoundwas prepared from 2-furfuryl isothiocyanate and3′-amino-2-(dimethylamino)acetanilide, derived from2-dimethylamino-3′-nitroacetanilide. MS(ESI): 373(MH⁺).

C. Preparation of2-dimethylamino-N-{3-[3-furan-2-ylmethyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-phenyl}acetamide

In a manner similar to Example 45, 2-mercapto-5-methoxybenzothiazole wasalkylated with methyl p-toluenesulfonate and then condensed with2-dimethylamino-N-[3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)-phenyl]acetamide. MS(ESI): 550(MH⁺).

EXAMPLE 167 Preparation of3-(3′-benzyl-3,4,5-trimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 3-chloro-2-butanone.MS(ESI): 476 (MH⁺).

EXAMPLE 168 Preparation of3-[3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 2-chlorocyclohexanone.MS(ESI): 502 (MH⁺).

EXAMPLE 169 Preparation of3-(3′-benzyl-4-ethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 1-bromo-2-butanone.MS(ESI): 476 (MH⁺).

EXAMPLE 170 Preparation of3-[3′-benzyl-3-methyl-4-(4-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitril

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-nitroacetophenone. MS(ESI): 569 (MH⁺).

EXAMPLE 171 Preparation of3-[3′-benzyl-4-(4-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-fluoroacetophenone. MS(ESI): 542 (MH⁺).

EXAMPLE 172 Preparation of3-[3′-benzyl-4-(4-chloro-phenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-chloroacetophenone. MS(ESI): 558 (MH⁺).

EXAMPLE 173 Preparation of3-(3′-benzyl-3-methyl-4′-oxo-4-p-tolyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-methylacetophenone. MS(ESI): 538 (MH⁺).

EXAMPLE 174 Preparation of3-[3′-benzyl-4-(4-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-methoxyacetophenone. MS(ESI): 554 (MH⁺).

EXAMPLE 175 Preparation of3-(5-acetyl-3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with3-chloro-2,4-pentanedione. MS(ESI): 504 (MH⁺).

EXAMPLE 176 Preparation of3-[3-benzyl-5-(3-methyl-3,4,5,6-tetrahydrocyclopentathiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-chlorocyclopentanone. MS(ESI): 488 (MH⁺).

EXAMPLE 177 Preparation of3-(3′-benzyl-3-methyl-4′-oxo-4,5-diphenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-chloro-2-phenylacetophenone. MS(ESI): 600 (MH⁺).

EXAMPLE 178 Preparation of3-(3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with chloroacetone.MS(ESI): 462 (MH⁺).

EXAMPLE 179 Preparation of4-ethylamino-3-[5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-iump-toluenesulfonate with4-ethylamino-3-(4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino)benzonitrile.MS(ESI): 503 (MH⁺).

EXAMPLE 180 A. Preparation of methyl4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoate

In a manner similar to Example 52, the title compound was prepared from3′-amino-4′-ethylaminoacetophenone and methyl4-(isothiocyantomethyl)benzoate—generated from methyl4-(aminomethyl)benzoate hydrochloride and thiophosgene. ¹H-NMR (CDCl₃):δ 8.04 (2H, d), 7.69 (1H, m), 7.58 (1H, s), 7.47 (2H, d), 6.52 (1H, d),5.10 (2H, s), 3.96 (2H, s), 3.92 (3H, s), 3.05 (2H, q), 2.49 (3H, s),1.03 (3H, t).

B. Preparation of methyl4-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate

The title compound was prepared from intermediate4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoicacid methyl ester and 3-methyl-2-(methylthio)benzothiazol-3-iump-toluenesulfonate in a manner similar to Example 45. ¹H-NMR (CDCl₃): δ8.03 (2H, d), 7.64–7.70 (2H, m), 7.49–7.55 (3H, m), 7.36 (1H, m), 7.20(1H, m), 7.08 (1H, d), 6.51 (1H, d), 5.24 (2H, s), 4.15 (1H, br t), 3.91(3H, s), 3.80 (3H, s), 3.04 (2H, m), 2.51 (3H, s), 1.01 (3H, s);MS(ESI): 573 (MH⁺).

EXAMPLE 181 Preparation of methyl4-[2-(5-acetyl-2-ethylamino-phenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-iump-toluenesulfonate with4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoicacid methyl ester. MS(ESI): 577 (MH⁺).

EXAMPLE 182 Preparation of4-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoicacid

The product of Example 180 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 559(MH⁺).

EXAMPLE 183 Preparation of3-[3-benzyl-5-(1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-thylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with3-bromo-4-oxopiperidine-1-carboxylic acid 9H-fluoren-9-ylmethylester—synthesized according to a published procedure [J. Med. Chem.1998, 41, 1409–1416].

¹H-NMR (CDCl₃): δ 7.39–7.43 (2H, m), 7.33 (2H, m), 7.24–7.29 (2H, m),7.20 (1H, d), 6.47 (1H, d), 5.15 (2H, s), 4.28 (1H, br t), 3.81 (2H, brs), 3.63 (3H, s), 3.22 (2H, br s), 2.99 (2H, q), 2.49 (2H, br s), 1.01(3H, t); MS(ESI): 503 (MH⁺).

EXAMPLE 184 Preparation of methyl3-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate

To a solution of methyl 3-(bromomethyl)benzoate (1.0 g, 4.4 mmol) inanhydrous DMF (10 mL) was added sodium azide (285 mg, 4.4 mmol). Theresulting mixture was heated at 50° C. for 2 h, cooled, diluted withCHCl₃ (100 mL), washed with water (5×50 mL), dried over MgSO₄ andconcentrated under reduced pressure to yield methyl3-(azidomethyl)benzoate (0.84 g, quant.), which was used withoutpurification. ¹H-NMR (CDCl₃): δ 8.01 (2H, m), 7.44–7.54 (2H, m), 4.42(2H, s), 3.94 (3H, s).

Methyl 3-(azidomethyl)benzoate was transformed into its amine(Staudinger conditions) and then converted into its isocyanate in amanner similar to Example 45. The title compound then was prepared in amanner similar to that described in Example 180 by replacing methyl4-(isothiocyantomethyl)benzoate with methyl3-(isothiocyantomethyl)benzoate.

¹H-NMR (CDCl₃): δ 8.13 (1H, br s), 7.98 (1H, d), 7.60–7.70 (3H, m), 7.53(1H, d), 7.43 (1H, m), 7.36 (1H, m), 7.20 (1H, m), 7.07 (1H, d), 6.52(1H, d), 5.24 (2H, s), 4.20 (1H, br t), 3.90 (3H, s), 3.79 (3H, s), 3.05(2H, m), 2.51 (3H, s), 1.01 (3H, t); MS(ESI): 573 (MH⁺).

EXAMPLE 185 Preparation of3-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoicacid

The product of Example 184 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 559(MH⁺).

EXAMPLE 186 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-iump-toluenesulfonate with2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one. MS(ESI):519 (MH⁺).

EXAMPLE 187 Preparation of3-(3′-benzyl-4-biphenyl-4-yl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-phenylacetophenone. MS(ESI): 600 (MH⁺).

EXAMPLE 188 Preparation of3-(3′-benzyl-3-methyl-4-naphthalen-2-yl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-acetonaphthone. MS(ESI): 574 (MH⁺).

EXAMPLE 189 Preparation of3-[3′-benzyl-4-(4-bromophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2,4′-dibromoacetophenone. MS(ESI): 602 (MH⁺).

EXAMPLE 190 Preparation of3-[3′-benzyl-3-methyl-4-(2-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-nitroacetophenone. MS(ESI): 569 (MH⁺).

EXAMPLE 191 Preparation of2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-iump-toluenesulfonate with2-(5-acetyl-2-ethylaminophenylimino)-3-pyridin-3-ylmethyl-thiazolidin-4-one.MS(ESI): 520 (MH⁺).

EXAMPLE 192 Preparation of3-[3′-benzyl-4-(2-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-methoxyacetophenone. MS(ESI): 554 (MH⁺).

EXAMPLE 193 Preparation of3-[3′-benzyl-4-(3-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-3′-fluoroacetophenone. MS(ESI): 542 (MH⁺).

EXAMPLE 194 Preparation of3-[3′-benzyl-3-methyl-4′-oxo-4-(4-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-trifluoromethyl-acetophenone. MS(ESI): 592 (MH⁺).

EXAMPLE 195 Preparation of3-[3′-benzyl-3-methyl-4′-oxo-4-(4-trifluoromethoxyphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-(trifluoromethoxy)acetophenone. MS(ESI): 608 (MH⁺).

EXAMPLE 196 Preparation of3-[3′-benzyl-4-(2,4-dimethoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′,4′-dimethoxyacetophenone. MS(ESI): 584 (MH⁺).

EXAMPLE 197 Preparation of3-(3′-benzyl-5-ethyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 2-bromobutyrophenone.MS(ESI): 552 (MH⁺).

EXAMPLE 198 Preparation of3-[3′-benzyl-3-methyl-4′-oxo-4-(2-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-(trifluoromethyl)acetophenone. MS(ESI): 592 (MH⁺).

EXAMPLE 199 Preparation of3-[3′-benzyl-4-(3-bromophenyl)-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2,3′-dibromopropiophenone. MS(ESI): 617 (MH⁺).

EXAMPLE 200 Preparation of3-[3′-benzyl-4-(3-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-3′-methoxyacetophenone. MS(ESI): 554 (MH⁺).

EXAMPLE 201 Preparation of3-benzyl-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)-phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing aniline with4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)aniline. MS(ESI): 596(MH⁺).

EXAMPLE 202 Preparation of3-(3′-benzyl-4-chloromethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 1,3-dichloroacetone.MS(ESI): 496 (MH⁺).

EXAMPLE 203 Preparation of3′-benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylicacid ethyl ester

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with ethyl bromopyruvate.MS(ESI): 520 (MH⁺).

EXAMPLE 204 Preparation of3-(4,3′-dibenzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with1-chloro-3-phenylpropan-2-one. MS(ESI): 538 (MH⁺).

EXAMPLE 205 Preparation of3′-benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylicacid

The product of Example 203 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 492(MH⁺).

EXAMPLE 206 Preparation of3-benzyl-2-[2-ethylamino-5-(1-hydroxyethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The product of Example 38 was reduced with sodium borohydride in 1:1MeOH/THF and chromatographed (TEA-washed silica gel, 0–10% MeOH/DCM) toafford the title compound. ¹H-NMR (CDCl₃): δ 7.47–7.54 (3H, m),7.28–7.37 (4H, m), 7.17 (1H, m), 6.99–7.06 (3H, m), 6.57 (1H, d), 5.19(2H, s), 4.80 (1H, q), 3.76 (3H, s), 3.01 (2H, q), 1.48 (3H, d), 1.04(3H, s); MS(ESI): 517 (MH⁺).

EXAMPLE 207 Preparation of3-[3′-benzyl-4-(2-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The product of Example 192 was treated with boron tribromide in DCM at25° C. After 15 min the product mixture was quenched with brine,concentrated and chromatographed (silica gel, 0–10% MeOH/DCM) to yieldthe title compound. MS(ESI): 540 (MH⁺).

EXAMPLE 208 Preparation of3-benzyl-2-[2-ethylamino-5-(1-hydroxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

To the product of Example 38 was added hydroxylamine hydrochloride (2equiv) and pyridine. The resulting mixture was heated at 80° C. for 24h, cooled, concentrated and chromatographed (TEA-washed silica gel,0–50% EtOAc/Hex) to give the title compound. ¹H-NMR (DMSO-d₆): δ 11.07(1H, s), 7.88 (1H, s), 7.67 (2H, m), 7.53 (1H, d), 7.39 (2H, m),7.21–7.33 (5H, m), 7.09–7.14 (1H, m), 5.05 (2H, s). 3.92 (2H, q), 3.27(3H, s), 2.23 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH⁺).

EXAMPLE 209 Preparation of3-benzyl-2-[2-ethylamino-5-(1-methoxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 208 by replacing hydroxylamine hydrochloride withO-methylhydroxylamine hydrochloride. MS(ESI): 544 (MH⁺).

EXAMPLE 210 Preparation of3-benzyl-2-[5-(1-benzyloxyiminoethyl)-2-ethylaminophenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 208 by replacing hydroxylamine hydrochloride withO-benzylhydroxylamine hydrochloride. MS(ESI): 620 (MH⁺).

EXAMPLE 211 Preparation of3-benzyl-2{2-ethylamino-5-[1-(phenylhydrazono)ethyl]-phenylimino}-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 208 by replacing hydroxylamine hydrochloride withphenylhydrazine. MS(ESI): 605 (MH⁺).

EXAMPLE 212 Preparation of3-(4,3′-dibenzyl-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with3-chloro-1-phenylbutan-2-one. MS(ESI): 552 (MH⁺).

EXAMPLE 213 Preparation of3-[3-cyclohexylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide withcyclohexylmethyl isothiocyanate. MS(ESI): 504 (MH⁺).

EXAMPLE 214 Preparation of3-[3′-benzyl-4-(3-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 200 in amanner similar to that described in Example 207. MS(ESI): 540 (MH⁺).

EXAMPLE 215 Preparation of3-[3′-benzyl-4-(4-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 174 in amanner similar to that described in Example 207. MS(ESI): 540 (MH⁺).

EXAMPLE 216 Preparation of3-(3′-benzyl-3,4-dimethyl-4′-oxo-5-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with1-chloro-1-phenylpropan-2-one—generated in situ by addition ofmethylmagnesium chloride to chlorophenylacetyl chloride (−78 to 25° C.).MS(ESI): 538 (MH⁺).

EXAMPLE 217 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3,5-dimethyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing 3-amino-4-ethylaminobenzonitrile with3′amino-4′-ethylaminoacetophenone. MS(ESI): 555 (MH⁺).

EXAMPLE 218 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3,4-dimethyl-5-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with1-chloro-1-phenylpropan-2-one. MS(ESI): 555 (MH⁺).

EXAMPLE 219 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(4-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with2-bromo-4′-methoxypropiophenone. MS(ESI): 585 (MH⁺).

EXAMPLE 220 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-4,3′-dibenzyl-3-methyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with1-chloro-3-phenylpropan-2-one. MS(ESI): 555 (MH⁺).

EXAMPLE 221 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(2-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with2-bromo-2′-methoxypropiophenone. MS(ESI): 585 (MH⁺).

EXAMPLE 222 Preparation of3-{3-benzyl-5-[5-(2-dimethylaminoacetyl)-1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

To the product of Example 183 in CHCl₃ was added N,N-dimethylaminoacetylchloride and TEA. After 4 h the product mixture was concentrated andchromatographed (silica gel, 0–40% EtOAc/Hex) to yield the titlecompound. ¹H-NMR (CDCl₃): δ 7.39–7.44 (2H, m), 7.33 (2H, m), 7.23–7.30(2H m), 7.19 (1H, brs), 6.47 (1H, d), 5.15 (2H, s), 4.61 (1H, brs), 4.51(1H, br s), 4.27 (1H, m), 3.92 (2H, m), 3.64 (3H, br s), 3.22 (1H, brs), 3.16 (1H, br s), 2.99 (2H, m), 2.63 (1H, br s), 2.56 (1H, br s),2.31 (3H, s), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 588 (MH⁺).

EXAMPLE 223 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with2-bromo-3′-methoxypropiophenone. MS(ESI): 585 (MH⁺).

EXAMPLE 224 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-hydroxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared from the product of Example 223 in amanner similar to that described in Example 207. MS(ESI): 571 (MH⁺).

EXAMPLE 225 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3,3′-dibenzyl-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium benzyldithiocarbamate—generated from benzylamine,carbon disulfide and TEA. MS(ESI): 631 (MH⁺).

EXAMPLE 226 Preparation ofN-(3-{3-benzyl-5-[5-(2-acetoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylamino-acetamide

To the product of Example 145 (21 mg, 32 μmol) in acetone (2 mL) wasadded tetra-n-butylammonium iodide (24 mg, 65 μmol). The solution wasstirred at 40° C. for 17 h prior to the addition of sodium acetate (50mg, 0.64 mmol). The reaction solution was heated at 75° C. for 48 h.After cooling the solution was diluted with EtOAc (25 mL), washed withsaturated NaHCO₃ (20 mL) and water (2×20 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The crude sample waschromatographed (silica gel, DCM) to provide the title compound (7 mg,33%). ¹H-NMR (CDCl₃) δ 7.87 (1H, s), 7.60 (1H, dd), 7.30–7.35 (3H, m),7.17–7.22 (3H, m), 6.60 (1H, dd), 6.48 (1H, d), 5.27 (2H, s), 4.72 (1H,s), 4.39 (2H, t), 4.16 (2H, t), 3.69 (2H, q), 3.16 (2H, s), 3.08 (3H,s), 2.43 (6H, s), 2.06 (3H, s), 0.91 (3H, t); MS(ESI): 675 (MH⁺).

EXAMPLE 227 Preparation of 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-methoxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium 2-methoxyethyldithiocarbamate—generated from2-methoxy-ethylamine, carbon disulfide and TEA. MS(ESI): 599 (MH⁺).

EXAMPLE 228 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(3-methoxypropyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium 3-methoxypropyldithiocarbamate—generated from2-methoxy-propylamine, carbon disulfide and TEA. MS(ESI): 613 (MH⁺).

EXAMPLE 229 Preparation of[2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]aceticacid methyl ester

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium methoxycarbonylmethyldithiocarbamate—generated fromglycine methyl ester, carbon disulfide and TEA. MS(ESI): 613 (MH⁺).

EXAMPLE 230 Preparation of[2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]aceticacid

The product of Example 229 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 599(MH⁺).

EXAMPLE 231 A. Preparation of2-(5-methyl-4-phenyl-2-thioxothiazol-3-yl)ethyl acetate

3-(2-Hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thione was preparedin a manner similar to that described in Example 52 by replacingtriethylammonium methyldithiocarbamate with triethylammonium2-hydroxyethyldithiocarbamate—generated from ethanolamine, carbondisulfide and TEA.

Intermediate 3-(2-hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thionewas treated with acetic anhydride (1 equiv) and TEA (2 equiv) in CHCl₃.After 12 h the product mixture was concentrated and chromatographed(silica gel, 0–40% EtOAc/Hex) to afford the title compound. ¹H-NMR(CDCl₃): δ 7.50–7.55 (3H, m), 7.28–7.32 (2H, m), 4.32 (2H, t), 4.26 (2H,t), 2.03 (3H, s), 1.93 (3H, s).

B. Preparation of2-[2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]ethylacetate

In a manner similar to that described in Example 52, intermediate2-(5-methyl-4-phenyl-2-thioxothiazol-3-yl)ethyl acetate was alkylatedwith methyl p-toluenesulfonate and condensed with2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to yieldthe title compound. ¹H-NMR (CDCl₃): δ 7.63–7.67 (2H, m), 7.44–7.51 (5H,m), 7.28–7.37 (5H, m), 6.50 (1H, d), 5.19 (2H, s), 4.30 (1H, br t), 4.03(4H, m), 3.06 (2H, m), 2.48 (3H, s), 2.05 (3H, s), 1.89 (3H, s), 1.05(3H, t); MS(ESI): 627 (MH⁺).

EXAMPLE 232 Preparation of2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-hydroxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The product of Example 231 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 585(MH⁺).

EXAMPLE 233 A. Preparation of3′-benzyl-3,5-dimethyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-methylthiobenzothiazole with3,5-dimethyl-4-phenyl-3H-thiazole-2-thione. ¹H-NMR (CDCl₃): δ 7.50–7.58(5H, m), 7.23–7.32 (5H, m), 5.39 (2H, s), 3.54 (3H, s), 2.11 (3H, s).

B. Preparation ofN-[3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-methoxyacetamide

Likewise as described in Example 1, intermediate3′-benzyl-3,5-dimethyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-onewas alkylated with methyl p-toluenesulfonate and condensed withN-(3-amino-4-ethylaminophenyl)-2-methoxyacetamide to afford the titlecompound. ¹H-NMR (CDCl₃): δ 8.00 (1H, brs), 7.42–7.51 (5H, m), 7.30–7.37(3H, m), 7.19–7.26 (3H, m). 7.11 (1H, d), 6.53 (1H, br s), 5.18 (2H, s),3.97 (2H, s), 3.47 (3H, s), 3.42 (3H, s), 2.98 (2H, m), 2.06 (3H, s),1.02 (3H, br t); MS(ESI): 600 (MH⁺).

EXAMPLE 234 Preparation ofN-[3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-dimethylaminoacetamide

The title compound was prepared in a manner similar to that described inExample 233 by replacingN-(3-amino-4-ethylaminophenyl)-2-methoxyacetamide withN-(3-amino-4-ethylaminophenyl)-2-dimethylaminoacetamide. MS(ESI): 613(MH⁺).

EXAMPLE 235 Preparation of3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

To a biphasic mixture of cyclohexylamine (2.3 mL, 20 mmol) in CHCl₃ (60mL) and saturated aqueous NaHCO₃ (40 mL) was added a solution of CSCl₂(1.57 mL, 20 mmol) in CHCl₃ (5 mL) dropwise at 5° C. The mixture wasstirred 1 h at 5° C. Methyl thioglycolate (1.9 mL, 20 mmol) was added,and the mixture was stirred overnight at 20° C. The organic layer wasseparated, and the aqueous layer was extracted with CHCl₃. The combinedorganic layers were washed with water, 1N HCl, water, saturated aqueousNaHCO₃ and then dried over MgSO₄. Evaporation of solvent under reducedpressure gave a crude material, which was used in the next step withoutpurification.

To a solution of the above product in toluene (80 mL) was added TsOH(100 mg), and the mixture was heated at reflux for 8 h with a droppingfunnel containing 4 Å molecular sieves attached to the flask. Aftercooling, solid was removed by filtration. Evaporation of the filtrategave a crude, which was purified by column chromatography on silica gel,eluting with EtOAc-Hex (0:100 to 3:7) to afford 3-cyclohexylrhodanine(1.24 g). ¹H-NMR (CDCl₃): δ 4.86 (1H, m), 3.82 (2H, s), 2.30 (2H, q),1.86 (2H, m), 1.58–1.72 (3H, m), 1.16–1.42 (3H, m).

The title compound was prepared in a manner similar to that described inExample 32 by replacing 3-benzylrhodanine with 3-cyclohexylrhodanine.MS(ESI): 490 (MH⁺).

EXAMPLE 236 Preparation of3-[3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 235 by replacing cyclohexylamine with allylamine. MS(ESI): 448(MH⁺).

EXAMPLE 237 Preparation of3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 236 by replacing 3-amino-4-ethylaminobenzonitrile with5-aminoquinoline. MS(ESI): 431 (MH⁺).

EXAMPLE 238 Preparation of3-allyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 236 by replacing 3-amino-4-ethylaminobenzonitrile with4-aminothymol hydrochloride. MS(ESI): 452 (MH⁺).

EXAMPLE 239 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 235 by replacing cyclohexylamine with aniline. MS(ESI): 484(MH⁺).

EXAMPLE 240 Preparation of3-cyclohexyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 235 by replacing 3-amino-4-ethylaminobenzonitrile with1-amino-2-naphthol hydrochloride. MS(ESI): 488 (MH⁺).

EXAMPLE 241 Preparation of3-allyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 236 by replacing 3-amino-4-ethylaminobenzonitrile with1-amino-2-naphthol hydrochloride. MS(ESI): 446 (MH⁺).

EXAMPLE 242 Preparation of2-(4-cyclohexylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-phenylthiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 239 by replacing 3-amino-4-ethylaminobenzonitrile with4-cyclohexylaniline. MS(ESI): 498 (MH⁺).

EXAMPLE 243 Preparation of3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with6-fluoro-2-mercaptobenzothiazole. MS(ESI): 516 (MH⁺).

EXAMPLE 244 Preparation of3-[3-benzyl-5-(5-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with5-chloro-2-mercaptobenzothiazole. MS(ESI): 532 (MH⁺).

EXAMPLE 245 Preparation of3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with6-ethoxy-2-mercaptobenzothiazole. MS(ESI): 542 (MH⁺).

EXAMPLE 246 Preparation of4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-propylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 235 by replacing cyclohexylamine with propylamine. MS(ESI): 450(MH⁺).

EXAMPLE 247 Preparation of3-[3-benzyl-5-(3-methyl-6-nitro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with2-mercapto-6-nitrobenzothiazole. MS(ESI): 543 (MH⁺).

EXAMPLE 248 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}acetamide

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with2-mercapto-6-acetamidobenzothiazole. MS(ESI): 555 (MH⁺).

EXAMPLE 249 Preparation of3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 245 in amanner similar to that described in Example 57. MS(ESI): 514 (MH⁺).

EXAMPLE 250 Preparation of ethylcarbamic acid2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylester

The title compound was prepared in a manner similar to that described inExample 58 by replacing dimethylcarbamoyl chloride with ethylisocyanate. MS(ESI): 585 (MH⁺).

EXAMPLE 251 Preparation of{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}aceticacid methyl ester

To a suspension of K₂CO₃ (41 mg, 5 equiv) in 2-butanone (2 mL) wereadded the product of Example 57 (31 mg, 0.06 mmol) and methyl2-bromoacetate (7 μL, 1.2 equiv). The resulting suspension was heated at75° C. overnight. After cooling, the reaction mixture was filtered, andthe filtrate was evaporated to give a crude material, which was purifiedby chromatography on silica gel, eluting with MeOH-DCM (0:100 to 3:97)to give the title compound (5 mg). ¹H-NMR (CDCl₃): δ 7.63 (1H, d),7.28–7.39 (6H, m), 7.13 (1H, d), 7.08 (1H, d), 6.84 (1H, dd), 6.62 (1H,d), 5.13 (2H, s), 4.98 (1H, t), 4.88 (2H, s), 3.79 (3H, s), 3.68 (3H,s), 3.05 (2H, m), 0.99 (3H, t); MS(ESI): 586 (MH⁺).

EXAMPLE 252 Preparation of2-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetamide

The title compound was prepared in a manner similar to that described inExample 251 by replacing methyl 2-bromoacetate with 2-bromoacetamide.MS(ESI): 571 (MH⁺).

EXAMPLE 253 Preparation of (2-chloroethyl)carbamic acid2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylester

The title compound was prepared in a manner similar to that described inExample 250 by replacing ethyl isocyanate with 2-chloroethylisocyanate.MS(ESI): 619 (MH⁺).

EXAMPLE 254 Preparation of3-{3-benzyl-5-[3-methyl-5-(2-methylaminoethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitril

To the product of Example 57 (62 mg, 0.12 mmol) in anhydrous DMF (2 mL)were added 1,2-dibromoethane (100 mL, 10 equiv) and anhydrous K₂CO₃ (166mg, 10 equiv). The suspension was shaken overnight at 60° C. in a sealedtube. After cooling, the reaction mixture was concentrated under reducedpressure, diluted with DCM and acetone, and filtered. The filtrate wasconcentrated to give a residue, which was purified by chromatography onsilica gel, eluting with MeOH-DCM (1:19) to give a yellow solid, whichwas used in the next step without further purification.

The above material was dissolved in 2M solution of methylamine in THF (3mL) and the solution was heated in a sealed tube for 40 h at 60° C.After cooling, the product mixture was concentrated to give a residue,which was purified by chromatography on silica gel, eluting withMeOH-DCM (1:19 to 1:9) to give the title compound (10 mg). ¹H-NMR(CDCl₃): δ 7.63 (1H, d), 7.28–7.39 (6H, m), 7.13 (1H, d), 7.03 (1H, d),6.85 (1H, dd), 6.62 (1H, d), 5.13 (2H, s), 4.98 (1H, t), 4.12 (2H, t),3.79 (3H, s), 3.05 (3H, m), 2.93 (2H, t), 2.3 (3H, s), 0.99 (3H, t);MS(ESI): 571 (MH⁺).

EXAMPLE 255 Preparation of3-{3-benzyl-5-[5-(3-hydroxypropoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 59 by replacing 2-bromoethanol with 3-bromopropanol. MS(ESI):572 (MH⁺).

EXAMPLE 256 Preparation of (3-chloropropyl)carbamic acid2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylester

The title compound was prepared in a manner similar to that described inExample 250 by replacing ethyl isocyanate with 3-chloropropylisocyanate.MS(ESI): 633 (MH⁺).

EXAMPLE 257 Preparation of3-(3-benzyl-5-{3-methyl-5-[2-(4-methylpiperazin-1-yl)-ethoxy]-3H-benzothiazol-2-ylidene}-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing morpholine with 1-methylpiperizine. MS(ESI): 640(MH⁺).

EXAMPLE 258 Preparation of3-{3-benzyl-5-[3-methyl-5-(2-piperidin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing morpholine with piperidine. MS(ESI): 625 (MH⁺).

EXAMPLE 259 Preparation of3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing morpholine with dimethylamine. ¹H-NMR (CDCl₃): δ7.43 (2H, m), 7.33 (1H, d), 7.29 (2H, m), 7.25–7.27 (5H, m), 7.20 (1H,d), 6.80 (1H, dd), 6.70 (1H, d), 6.49 (1H, d), 5.18 (2H, s), 4.22 (1H,t), 4.11 (2H, t), 3.77 (3H, s), 3.00 (2H, m), 2.75 (2H, t), 2.35 (6H,s), 1.02 (3H, t), MS(ESI): 585 (MH⁺).

EXAMPLE 260 Preparation of{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}aceticacid

To the product of Example 57 (158 mg, 0.31 mmol) in anhydrous DMF (5 mL)were added tert-butyl bromoacetate (460 μL, 10 equiv) and anhydrousK₂CO₃ (425 mg, 10 equiv). The suspension was heated at 80° C. undernitrogen for 16 h. After cooling, resulting solids were removed byfiltration. The filtrate was concentrated to give a residue, which waspurified by chromatography on silica gel, eluting with MeOH-DCM (5:95)to give the product, which was used in the next step without furtherpurification.

The above product was dissolved in a 1:1 mixture of TFA/DCM (2 mL) andthe solution was stirred for 1 h at 20° C. Evaporation of solvent gave aresidue, which was purified by chromatography on silica gel, elutingwith MeOH-DCM (5:95) to give the title compound (35 mg, 75%). ¹H-NMR(CDCl₃): δ 7.61 (1H, m), 7.28–7.39 (6H, m), 7.13 (1H, d), 7.05 (1H, d),6.82 (1H, dd), 6.62 (1H, d), 5.14 (2H, s), 4.95 (1H, t), 4.76 (2H, t),3.79 (3H, s), 3.05 (2H, m), 0.99 (3H, t), MS(ESI): 572 (MH⁺).

EXAMPLE 261 Preparation of3-{3-benzyl-5-[6-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 59 by replacing the product of Example 57 with the product ofExample 249. MS(ESI): 558 (MH⁺).

EXAMPLE 262 Preparation of3-{3-benzyl-5-[6-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in the same manner as described inExample 261 in the presence of excess methyl p-toluenesulfonate.MS(ESI): 572 (MH⁺).

EXAMPLE 263 Preparation of3-{3-benzyl-5-[3-methyl-6-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing the product of Example 60 with the product ofExample 261. MS(ESI): 627 (MH⁺).

EXAMPLE 264 Preparation of3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in the same manner as described inExample 59 in the presence of excess methyl p-toluenesulfonate. MS(ESI):572 (MH⁺).

EXAMPLE 265 A. Preparation of 4-methoxy-2-methylthiobenzothiazole

2-Amino-4-methoxybenzothiazole (3.6 g, 20 mmol) was dissolved in warmH₃PO₄ (120 mL). The resulting homogeneous solution was cooled to −8° C.,and a solution of NaNO₂ (8.28 g, 120 mmol) in H₂O (50 mL) was addeddropwise with stirring such that the temperature was not allowed to riseabove −4° C. The resulting dark-red syrup was added slowly to H₃PO₂ (50%in H₂O, 60 mL) at 0° C. with stirring. After the addition was complete,the mixture was allowed to warm to ambient temperature until gasevolution had ceased. The solution was diluted with ice-water,cautiously neutralized with solid Na₂CO₃, and extracted with CHCl₃(3×200 mL). The combined extracts were washed with water (2×200 mL),dried over Na₂SO₄, and concentrated under reduced pressure to give a redsolid (2.87 g), which was purified by chromatography on silica gel,eluting with EtOAc-Hex (0:100 to 30:70) to yield 4-methoxybenzothiazole(2.14 g, 65%) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.90 (1H, s), 7.52(1H, d), 7.38 (1H, t), 6.93 (1H, d), 4.06 (3H, s).

To a solution of 4-methoxybenzothiazole (495 mg, 3.0 mmol) in anhydrousTHF (12 mL) at −78° C. was added BuLi (2.5 mL, 1.6M in hexanes, 4.0mmol) dropwise. The resulting red solution was stirred at −78° C. for 2h under N₂. Methyl disulfide (0.55 mL, 6.0 mmol) was added dropwise at−78° C. and the mixture was allowed to warm to ambient temperatureovernight. The reaction mixture was combined with water and thenextracted with EtOAc. The combined extracts were washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure to afford thetitle compound as a yellow oil (632 mg, 100%), which solidified uponstanding and was used without purification. ¹H-NMR (CDCl₃): δ 7.35 (1H,d), 7.24 (1H, q), 6.86 (1H, d), 4.06 (3H, s), 2.79 (3H, s).

B. Preparation of3-{3-benzyl-5-[3-methyl-4-methoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

To a suspension of the 4-methoxy2-methylthiobenzothiazole (0.60 g, 2.8mmol) in anhydrous anisole (8 mL) was added methyl p-toluenesulfonate(1.4 mL, 9.0 mmol) and the suspension was heated at 130° C. for 3.5 h.After cooling to 20° C., MeCN (5 mL),3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile(119 mg, 0.34 mmol) and TEA (2.0 mL, 14 mmol) were added. The suspensionwas stirred for 5 h at 80° C. After cooling to ambient temperature,yellow solids were collected by filtration, washed with MeCN and driedunder high vacuum to afford the title compound (123 mg, 69%). ¹H-NMR(CDCl₃): δ 7.45–7.11 (9H, m), 6.88–6.85 (1H, m), 6.48 (1H, d), 5.17 (2H,s), 4.08 (3H, s), 3.92 (3H, s), 3.02–2.97 (2H, m), 1.02 (3H, t); MS(ESI): 528 (MH⁺).

EXAMPLE 266 Preparation of3-{3-benzyl-5-[3-methyl-4-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-4-methylbenzothiazole. ¹H-NMR(CDCl₃): δ 7.46–7.06 (10H, m), 6.49 (1H, d), 5.17 (2H, s), 3.88 (3H, s),3.04–2.97 (2H, m), 2.62 (3H, s), 1.03 (3H, t); MS (ESI): 512 (MH⁺).

EXAMPLE 267 Preparation of3-{3-benzyl-5-[3-methyl-4-chloro-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-4-chlorobenzothiazole. ¹H-NMR(CDCl₃): δ 7.45–7.08 (10H, m), 6.50 (1H, d), 5.17 (2H, s), 4.01 (3H, s),3.04–2.98 (2H, m), 1.03 (3H, t); MS(ESI): 532 (MH⁺).

EXAMPLE 268 Preparation of3-{3-benzyl-5-[3-methyl-6-trifluoromethoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-6-(trifluoromethoxy)benzothiazole.

¹H-NMR (CDCl₃): δ 7.44–7.18 (9H, m), 7.06 (1H, d), 6.49 (1H, d), 5.17(2H, s), 3.81 (3H, s), 3.04–2.97 (2H, m), 1.03 (3H, t); MS(ESI): 582(MH⁺).

EXAMPLE 269 Preparation of3-[3-benzyl-5-(3,5,6-trimethyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-5,6-dimethylbenzothiazole. ¹H-NMR(CDCl₃): δ 7.44–7.20 (8H, m), 6.90 (1H, s), 6.48 (1H, d), 5.17 (2H, s),3.80 (3H, s), 3.03–2.97 (2H, m), 2.35 (3H, s), 2.31 (3H, s), 1.02 (3H,t); MS(ESI): 526 (MH⁺).

EXAMPLE 270 A. Preparation of 5-acetamidobenzothiazole

To a stirred solution of 4-chloro-3-nitroaniline (17.3 g, 100 mmol) inDCM (150 mL) was added dropwise acetic anhydride (14 mL, 150 mmol) atambient temperature. The mixture was stirred at ambient temperature for2.5 h. The solvent was removed in vacuo, and Et₂O was added to theresidue. The precipitate was collected by filtration, washed with Et₂O,and dried in vacuo to give N-(4-chloro-3-nitrophenyl)acetamide (20.7 g,96%), which was used without further purification.

A suspension of the above compound (13.8 g, 64.3 mmol) and Na₂S.9H₂O(18.6 g, 77.2 mmol) in DMF (100 mL) was stirred at ambient temperatureunder N₂ overnight. The reaction mixture was filtered, and the filtratewas diluted with water (400 mL) and then acidified with conc HCl to pH3. The resulting yellow solids were collected by filtration, washed withwater and dried under high vacuum to afford4′-mercapto-3′-nitroacetanilide (12.0 g, 88%).

A suspension of 4′-mercapto-3′-nitroacetanilide (3.0 g, 14 mmol) and 10%Pd/C (0.6 g) in MeOH (200 mL) was hydrogenated at 60 psi overnight. Thecatalyst was removed by filtration, and the filtrate was concentrated togive 3′-amino-4′-mercaptoacetanilide (2.5 g, 13 mmol), which was used inthe next reaction immediately.

To a solution of intermediate 3′-amino-4′-mercaptoacetanilide in HOAc(50 mL) was added ethoxymethylene malononitrile (1.95 g, 16 mmol) andthe resulting mixture was refluxed at 125° C. for 5 h. After cooling,the product mixture was concentrated under reduced pressure, and theresidue was partitioned between saturated aqueous NaHCO₃ and EtOAc. Theaqueous phase was extracted with EtOAc, and the combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel, eluting with EtOAc-Hex (0:100to 50:50) to give the title compound (508 mg, 17%) as a yellow solid.¹H-NMR (DMSO-d₆): δ 9.35 (1H, s), 8.53 (1H, s), 8.10 (1H, d), 7.63 (1H,d), 2.15 (3H, s).

B. Preparation of3-[3-benzyl-5-(3-methyl-5-acetamido-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared using the above 5-acetamidobenzothiazoleas the starting material in a manner similar to that described inExample 265. ¹H-NMR (CDCl₃): δ 7.45–7.21 (8H, m), 6.62 (1H, dd), 6.48(1H, d), 6.34 (1H, d), 5.17 (2H, s), 3.79 (3H, s), 3.02 (3H, s), 3.00(2H, m), 1.02 (3H, t); MS(ESI): 555 (MH⁺).

EXAMPLE 271 A. Preparation of2-methylthio-6-(trifluoroacetoamido)benzothiazole

To a suspension of 6-amino-2-mercaptobenzothiazole (550 mg, 3.0 mmol) inanhydrous MeCN (15 mL) was added TEA (0.9 mL) and methylp-toluenesulfonate (0.45 mL, 3.0 mmol) at ambient temperature. Themixture turned to a clear solution after a few minutes and was stirredat ambient temperature for 3 h. To the above solution was added dropwiseTFAA (0.65 mL, 4.6 mmol). After 12 h the solution was concentrated underreduced pressure, diluted with EtOAc, washed with water and brine, driedover Na₂SO₄ and concentrated. The resulting residue was purified bychromatography on silica gel, eluting with EtOAc-Hex (0:100 to 10:90) togive the title compound (575 mg, 66%) as a white solid. ¹H-NMR (CDCl₃):δ 8.31 (1H, d), 7.99 (1H, br s), 7.84 (1H, d), 7.35 (1H, dd), 2.80 (3H,s).

B. Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-6-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide

The title compound was prepared in a manner similar to that described inExample 265 by starting with2-methylthio-6-(trifluoroacetamido)benzothiazole. ¹H-NMR (DMSO-d₆): δ7.82 (1H, d), 7.40–7.06 (8H, m), 6.90 (1H, d), 6.48 (1H, d), 6.40 (1H,d), 4.89 (2H, s), 3.57 (3H, s), 2.83 (2H, m), 0.77 (3H, t); MS(ESI): 609(MH⁺).

EXAMPLE 272 Preparation of3-[5-(6-amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

To the product of Example 271 (400 mg, 0.66 mmol) in a mixture ofMeOH/H₂O (12 mL, 5:1 v/v) was added potassium carbonate (553 mg, 4.0mmol). The reaction mixture was stirred at 60° C. for 16 h, and thenconcentrated under reduced pressure. The resulting residue waspartitioned between CHCl₃ and water. The aqueous phase was extractedwith CHCl₃, and the combined extracts were washed with brine, dried overNa₂SO₄, and concentrated to give the title compound (326 mg, 97%) as ayellow solid. ¹H-NMR (DMSO-d₆): δ 7.40–7.28 (6H, m), 7.15–7.13 (2H, m),6.88 (1H, d), 6.66–6.61 (2H, m), 5.23 (2H, br s), 5.11 (2H, s), 3.75(3H, s), 3.09–3.02 (2H, m), 1.01 (3H, t); MS(ESI): 513 (MH⁺).

EXAMPLE 273 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N′,N″-di(tert-butoxycarbonyl)guanidine

To a stirred mixture of the product of Example 272 (77 mg, 0.15 mmol),N,N′-di-(tert-butoxycarbonyl)thiourea (50 mg, 0.18 mmol) and TEA (70 μL,0.5 mmol) in anhydrous DMF (1.5 mL) at 0° C. was added HgCl₂ (49 mg,0.18 mmol). The resulting mixture was stirred at 0° C. for 30 min, thenat ambient temperature overnight. The mixture was diluted with CHCl₃,washed with water and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith MeOH-DCM (0:100 to 20:80) to afford the title compound (98 mg,87%). ¹H-NMR (CDCl₃): δ 11.62 (1H, br s), 10.43 (1H, br s), 8.02 (2H,m), 7.45–7.20 (7H, m), 7.02 (1H, d), 6.49 (1H, t), 5.16 (2H, s), 3.82(3H, s), 3.04–2.96 (2H, m), 1.43 (9H, s), 1.35 (9H, s), 1.02 (3H, t);MS(ESI): 756 (MH⁺).

EXAMPLE 274 Preparation of2-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-1,1,-dimethylurea

To the product of Example 272 (89 mg, 0.174 mmol) in anhydrous CHCl₃ (5mL) were added TEA (0.3 mL, 2.4 mmol) and dimethylcarbamyl chloride (0.2mL, 2.0 mmol). The resulting mixture was stirred at ambient temperatureovernight. After diluting with CHCl₃, the mixture was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith MeOH-DCM (0:100 to 5:95) to afford the title compound (48 mg, 47%).¹H-NMR (CDCl₃): δ 7.70 (1H, d), 7.44–7.26 (8H, m), 7.20 (1H, d), 7.00(1H, d), 6.48 (1H, d), 6.38 (1H, s), 5.16 (2H, s), 3.79 (3H, s), 3.06(6H, s), 3.05–2.97 (2H, m), 1.02 (3H, t); MS(ESI): 584(MH⁺).

EXAMPLE 275 A. Preparation of 5-acetamido-2-mercaptobenzothiazole

To a stirred solution of 4-chloro-3-nitroaniline (51.8 g, 0.36 mol) inanhydrous DCM (300 mL) was added dropwise acetic anhydride (45 mL, 0.48mol) at room temperature, and the resulting solution was stirred at roomtemperature for 3 h. The solvent was removed in vacuo, and Et₂O wasadded to the residue. The precipitates were collected by filtration,washed thoroughly with Et₂O, and dried under high vacuum to give4′-chloro-3′-nitroacetanilide (78.7 g, 100%).

A mixture of Na₂S.9H₂O (65 g, 0.28 mol), sulfur (25 g, 0.78 mol) andwater (150 mL) were heated with stirring at 90° C. for 10 min, and thenpoured into a flask charged with the above 4′-chloro-3′-nitroacetanilide(21.5 g, 0.10 mol). The resulting mixture was heated at 80° C. for 10min, and then CS₂ (12 mL, 0.2 mol) was added dropwise while maintaininga gentle reflux. The resulting mixture was heated at 90° C. for 7 h. Thesolids were collected by filtration, washed with water and dilute HClsolution. The solids were taken up in water, and the solution was madealkaline with solid NaOH. The solution was filtered, and the filtratewas acidified with conc HCl. The precipitates were collected byfiltration, washed with water, and dried under high vacuum. The crudeproduct was suspended in cold water (200 mL) and solid Na₂CO₃ was addedto obtain pH 13. Dimethylsulfate was added to the above milky solution,and the resulting mixture was stirred at ambient temperature for 3 h.The solids were collected by filtration, washed with water, and driedunder high vacuum to yield the title compound (12.4 g, 55%).

B. Preparation of 2-methylthio-5-(2,2,2-trifluoroacetamido)benzothiazole

A suspension of 5-acetamido-2-mercaptobenzothiazole (12.9 g, 54 mmol) ina mixture of conc HCl (30 mL) and water (60 mL) was heated at reflux for3 h. After cooling, the mixture was extracted with CHCl₃, and theaqueous phase was diluted with ice-water. To the aqueous layer was addedportionwise solid NaOH to achieve pH 6, and then solid K₂CO₃ to obtainpH 8. The precipitates were collected by filtration, washed with water,and dried under high vacuum to yield 5-amino-2-methylthiobenzothiazole(7.65 g, 72%).

To a stirred solution of 5-amino-2-methylthiobenzothiazole (3.93 g, 20mmol) in anhydrous MeCN were added dropwise at 0° C. TFAA (4.0 mL, 28mmol) and TEA (5 mL, 36 mmol) under N₂. The mixture was stirred at roomtemperature for 3 h. The solvent was removed in vacuo, and the residuewas taken up in EtOAc, washed with water and brine, dried with Na₂SO₄,and concentrated in vacuo. The crude material was purified bychromatography on silica gel, eluting with EtOAc-Hex (0:100 to 20:80) toafford the title compound (3.9 g, 67%) as a pale white solid. ¹H-NMR(CDCl₃): δ 8.10 (1H, d), 7.98 (1H, br s), 7.75 (1H, d), 7.53–7.51 (1H,dd), 2.80 (3H, s).

C. Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide

The title compound was prepared from2-methylthio-5-trifluoroacetoamido-benzothiazole in a manner similar tothat described in Example 265. ¹H-NMR (DMSO-d₆): δ 7.82 (1H, d),7.56–7.26 (8H, m), 7.16 (1H, d), 6.51 (1H, d), 5.16 (2H, s), 3.83 (3H,s), 3.03–2.96 (2H, m), 1.02 (3H, t); MS(ESI): 609 (MH⁺).

EXAMPLE 276 Preparation of3-[5-(5-amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 275 in amanner similar to that described in Example 272. ¹H-NMR (DMSO-d₆): δ8.38 (1H, s), 7.47–7.36 (6H, m), 7.21 (1H, d), 6.69 (1H, d), 6.61–6.56(2H, m), 4.45 (2H, br s), 5.18 (2H, s), 3.78 (3H, s), 3.12 (2H, m), 1.06(3H, t) MS(ESI): 513 (MH⁺).

EXAMPLE 277 Preparation of{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}carbamicacid ethyl ester

The title compound was prepared in a manner similar to that described inExample 274 by replacing dimethylcarbamyl chloride with ethylchoroformate. ¹H-NMR (DMSO-d₆): δ 9.64 (1H, s), 7.75 (1H, d), 7.29–7.16(8H, m), 7.02 (1H, d), 6.51 (1H, d), 5.00 (2H, s), 4.04–3.98 (2H, q),3.68 (3H, s), 2.97–2.91 (2H, m), 1.26 (3H, t), 0.88 (3H, t); MS(ESI):585 (MH⁺).

EXAMPLE 278 Preparation ofN-[2-(3-benzyl-2-{5-cyano-2-[ethyl-(2-morpholinylethyl)amino]phenylimino}-4-oxothiazilidin-5-ylidene)-3-methyl-2,3-dihydrobenzothiazol-6-yl]-2,2,2-trifluoroacetamide

Sodium hydride (8 mg, 60% w/w in mineral oil, 0.2 mmol) was added at 0°C. to a stirred solution of the product of Example 271 (52 mg, 0.1 mmol)in anhydrous DMF under N₂. The mixture was stirred at 0° C. for 5 min,then at ambient temperature for 15 min. 4-(2-Chloroethyl)morpholinehydrochloride (24 mg, 0.15 mmol) was added to the above red solution at0° C., and the mixture was stirred at ambient temperature under N₂ for21 h. The reaction mixture was diluted with CHCl₃, washed thoroughlywith water, dried over Na₂SO₄, and concentrated under reduced pressure.The residue was purified by chromatography on silica gel, eluting withMeOH-DCM (0:100 to 20:80) to afford the title compound (42 mg, 58%) as ayellow solid. ¹H-NMR (CDCl₃): δ 8.98 (1H, br s), 7.92 (1H, s), 7.68 (1H,s), 7.51–7.22 (7H, m), 6.81 (1H, d), 5.12 (2H, s), 4.04 (2H, m), 3.64(5H, m), 3.36 (2H, m), 2.54–2.17 (8H, m), 1.26 (3H, m); MS(ESI): 722(MH⁺).

EXAMPLE 279 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide

To the product of Example 271 (65 mg, 0.11 mmol) in anhydrous DMF wereadded 4-(2-chloroethyl)morpholine hydrochloride (50 mg, 0.3 mmol), K₂CO₃(30 mg, 0.21 mmol) and KI (10 mg). The reaction mixture was heated at90° C. for 30 h, cooled, and diluted with CHCl₃. The solution was washedwith water, dried over Na₂SO₄, and concentrated in vacuo. The crudematerial was purified by chromatography on silica gel, eluting withMeOH-DCM (0:100 to 20:80) to afford the title compound (72 mg, 94%) as ayellow solid. ¹H-NMR (CDCl₃): δ 7.51 (1H, s), 7.44–7.42 (2H, m),7.38–7.28 (5H, m), 7.19 (1H, d), 7.09 (1H, d), 5.18 (2H, s), 4.21 (2H,br s), 3.85 (3H, s), 3.68 (4H, br s), 3.05–2.96 (2H, m), 2.52–2.45 (6H,m), 1.03 (3H, t); MS(ESI): 722 (MH⁺).

EXAMPLE 280 Preparation of3-{3-benzyl-5-[3-methyl-6-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 279 in amanner similar to that described in Example 272. ¹H-NMR (CDCl₃): δ7.44–7.21 (7H, m), 6.93 (1H, d), 6.78 (1H, d), 6.65 (1H, m), 6.48 (1H,d), 5.17 (2H, s), 3.81 (3H, s), 3.80–3.74 (4H, m), 3.20–3.17 (2H, m),3.03–2.96 (2H, m), 2.67 (2H, br s), 2.49 (4H, br s), 1.02 (3H, t);MS(ESI): 626 (MH⁺).

EXAMPLE 281 Preparation of3-{3-benzyl-5-[3-methyl-6-(2-piperidin-1-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 4-(2-chloroethyl)piperidine hydrochloride. ¹H-NMR(CDCl₃): δ 7.44–7.19 (7H, m), 6.93 (1H, d), 6.77–6.71 (2H, m), 6.48 (1H,d), 5.16 (2H, s), 3.77 (3H, s), 3.28 (2H, br s), 3.03–2.96 (2H, m), 2.81(2H, br s), 2.48 (2H, br s), 2.04 (4H, br s), 1.02 (3H, t); MS(ESI): 624(MH⁺).

EXAMPLE 282 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide

The title compound was prepared from the product of Example 275 in amanner similar to that described in Example 279. ¹H-NMR (CDCl₃): δ 7.54(1H, d), 7.44–7.11 (9H, m), 6.50 (1H, d), 5.18 (2H, s), 3.95 (2H, m),3.79 (3H, s), 3.70 (4H, m), 3.04–2.98 (2H, m), 2.49 (6H, m), 1.03 (3H,t); MS(ESI): 722 (MH⁺).

EXAMPLE 283 Preparation of3-{3-benzyl-5-[3-methyl-5-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 282 in amanner similar to that described in Example 272. ¹H-NMR (CDCl₃): δ 7.54(1H, d), 7.44–7.11 (9H, m), 6.50 (1H, d), 5.18 (2H, s), 3.80 (2H, s),3.70 (4H, br s), 3.04–2.98 (2H, m), 2.49 (6H, br s), 1.03 (3H, t);MS(ESI): 626 (MH⁺).

EXAMPLE 284 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}guanidine

To a stirred solution of the product of Example 273 (116 mg, 0.15 mmol)in anhydrous DCM (6 mL) was added TFA (3 mL) at 0° C. The reactionmixture was stirred at 0° C. for 30 min, then at ambient temperature for14 h. The solvent was removed in vacuo, and the residue was purified byreverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H₂O (1:9to 9:1) to afford the title compound (25 mg, 30%) as a yellow solid.¹H-NMR (DMSO-d₆): δ 9.65 (1H, s), 7.72 (1H, d), 7.48 (1H, d), 7.41–7.25(8H, m), 7.15 (1H, d), 6.65 (1H, d), 5.14 (2H, s), 3.84 (3H, s), 3.07(2H, m), 1.01 (3H, t); MS(ESI): 555 (MH⁺).

EXAMPLE 285 Preparation of3-{3-benzyl-5-[3-methyl-6-(4-trifluoromethylbenzylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 4-(trifluoromethyl)benzyl bromide. ¹H-NMR (DMSO-d₆):δ 7.69 (2H, d), 7.58 (2H, d), 7.38–7.32 (6H, m), 7.17 (1H, d), 7.14 (1H,d), 6.94 (1H, d), 6.63 (1H, dd), 6.61 (1H, d), 5.10 (2H, s), 4.40 (2H,s), 3.73 (3H, s), 3.05 (2H, m), 1.00 (3H, t); MS(ESI): 671 (MH⁺).

EXAMPLE 286 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-fluoropropyl)-2,2,2-trifluoroacetamide

The title compound was prepared in a manner similar to that described inExample 279 by replacing 4-(2-chloroethyl)morpholine hydrochloride with1-bromo-3-fluoropropane. ¹H-NMR (CDCl₃): δ 7.44–7.19 (9H, m), 7.10 (1H,d), 6.50 (1H, d), 5.18 (2H, s), 4.60 (1H, m), 4.48 (1H, m), 4.20 (1H,m), 3.91 (1H, m), 3.83 (3H, s), 3.01 (2H, m), 2.09–1.99 (2H, m), 1.03(3H, t); MS(ESI): 669 (MH⁺).

EXAMPLE 287 Preparation ofN-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-cyanopropyl)-2,2,2-trifluoroacetamide

The title compound was prepared in a manner similar to that described inExample 279 by replacing 4-(2-chloroethyl)morpholine hydrochloride with4-bromobutyronitrile. ¹H-NMR (CDCl₃): δ 7.44–7.19 (9H, m), 7.11 91H, d),6.51 91H, d), 5.19 (2H, s), 3.86 (3H, s), 3.85–3.77 (2H, m), 3.05–2.98(2H, m), 2.53–2.44 (2H, m), 2.04–1.88 (2H, m), 1.03 (3H, t); MS(ESI):676 (MH⁺).

EXAMPLE 288 Preparation of3-{3-benzyl-5-[6-(3-cyanopropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

The title compound was prepared from the product of Example 287 in amanner similar to that described in Example 272. ¹H-NMR (CDCl₃): δ7.44–7.20 (7H, m), 6.94 (1H, d), 6.77 (1H, d), 6.65 (1H, dd), 6.48 (1H,d), 5.17 (2H, s), 3.77 (3H, s), 3.34 (2H, m), 3.01 (2H, m), 2.49 (2H,m), 2.01 (2H, m), 1.02 (3H, t); MS(ESI): 580 (MH⁺).

EXAMPLE 289 Preparation of3-{3-benzyl-5-[6-(3-hydroxypropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 3-bromopropanol. ¹H-NMR (CDCl₃): δ 7.44–7.21 (8H, m),6.93 (1H, d), 6.79 (1H, d), 6.65 (1H, dd), 6.48 (1H, d), 5.17 (2H, s),3.85 (2H, m), 3.77 (3H, s), 3.30 (2H, t), 3.01 (2H, m), 1.92 (2H, m),1.02 (3H, t); MS(ESI): 571 (MH⁺).

EXAMPLE 290 Preparation of3-{3-benzyl-5-[6-(2-methoxyethylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamine)benzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 2-bromoethyl methyl ether. ¹H-NMR (CDCl₃): δ7.44–7.21 (7H, m), 6.93 (1H, d), 6.79 (1H, d), 6.66 (1H, dd), 6.48 (1H,d), 5.17 (2H, s), 3.77 (3H, s), 3.63 (2H, m), 3.41 (3H, s), 3.30 (2H,m), 3.00 (2H, m), 1.02 (3H, t); MS(ESI): 571 (MH⁺).

EXAMPLE 291 In Vivo Studies

In order to evaluate direct regulation of key target genes by thecompounds of the invention, animals are administered a single oral doseof the test compound and tissues collected at six or fifteen hours afterdose. Male C57BL/6 mice (n=8) are dosed by oral gavage with vehicle orcompound. At six and fifteen hours after the dose, animals are bled viathe retro orbital sinus for plasma collection. Animals are theneuthanized and tissues, such as liver and intestinal mucosa arecollected and snap frozen for further analysis. Plasma is analyzed forlipid parameters, such as total cholesterol, HDL cholesterol andtriglyceride levels. RNA is extracted from frozen tissues and can beanalyzed by quantitative real time PCR for regulation of key targetgenes. To identify specificity of target gene regulation by FXR, knockout mice (FXR^(−/−)) and C57BL/6 wild-type controls may be used in thissame protocol.

Plasma Lipid Evaluation

To compare the effects of compounds on plasma cholesterol andtriglycerides, animals are dosed with compound for one week and plasmalipid levels are monitored throughout the study. Male C57BL/6 mice (n=8)are dosed daily by oral gavage with vehicle or compound. Plasma samplesare taken on day −1 (in order to group animals), day 1, 3, and 7.Samples are collected three hours after the daily dose. On day 7 of thestudy, following plasma collection, animals are euthanized and tissues,such as liver and intestinal mucosa are collected and snap frozen forfurther analysis. Plasma is analyzed for lipid parameters, such as totalcholesterol, HDL cholesterol and triglyceride levels. RNA is extractedfrom frozen tissues and can be analyzed by quantitative real time PCRfor regulation of key target genes. To identify specificity of targetgene regulation by FXR knockout mice and C57BL/6 wild-type controls[maybe] may be used in this same protocol.

Cholesterol Absorption

Evaluation of compounds to inhibit cholesterol absorption is done viameasurement of labeled cholesterol in feces. Male A129 mice (n=7) aredosed daily by oral gavage with vehicle or compound for 7 days. On day 7of the study, animals are administered [¹⁴C]-cholesterol and[³H]-sitostanol by oral gavage. Animals are individually housed on wireracks for the next 24 hours in order to collect feces. Feces are thendried and ground to a fine powder. Labeled cholesterol and sitostanolare extracted from the feces and ratios of the two are counted on aliquid scintillation counter in order to evaluate the amount ofcholesterol absorbed by the individual animal.

Since modifications will be apparent to those of skill in this art, itis intended that the subject matter claimed herein be limited only bythe scope of the appended claims.

1. A pharmaceutical composition, comprising: (a) a compound of formulaeI:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orsubstituted or unsubstituted heteroaralkyl, substituted or unsubstitutedheteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² andC(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selectedfrom hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O,S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) one or more of the following: anantihyperlipidemic agent, a plasma HDL-raising agent, ananti-hypercholesterolemic agent, a cholesterol biosynthesis inhibitor,an acyl-coenzyme A:cholesterol acytransferase (ACAT) inhibitor,probucol, raloxifene, nicotinic acid, niacinamide, a cholesterolabsorption inhibitor, a bile acid sequestrant, a low density lipoproteinreceptor inducer, clofibrate, fenofibrate, benzofibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, an anti-oxidant vitamin, aβ-blocker, an anti-diabetes agent, an angiotensin II antagonist, anangiotensin converting enzyme inhibitor, a platelet aggregationinhibitor, a fibrinogen receptor antagonist, aspirin or a fibric acidderivative.
 2. The composition of claim 1, wherein the cholesterolbiosynthesis inhibitor is an HMG CoA reductase inhibitor.
 3. Thecomposition of claim 2, wherein the HMG CoA reductase inhibitor islovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin orrivastatin.
 4. The composition of claim 3, wherein the HMG CoA reductaseinhibitor is lovastatin or simvastatin.
 5. The composition of claim 1,wherein the bile acid sequestrant is an anion exchange resin or aquaternary amine.
 6. The composition of claim 1, wherein the quaternaryamine is cholestyramine or colestipol.
 7. A pharmaceutical composition,comprising: (a) a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand C are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and F togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) one or more of the following: anantihyperlipidemic agent, a plasma HDL-raising agent, anantihypercholesterolemic agent, an HMG-CoA synthase inhibitor, asqualene epoxidase inhibitor, a squalene synthetase inhibitor, anacyl-coenzyme A cholesterol acyltransferase inhibitor, probucol,nicotinic acid or a salt thereof, niacinamide, a cholesterol absorptioninhibitor, a bile acid sequestrant anion exchange resin, a low densitylipoprotein receptor inducer, a fibrate, vitamin B₆ or apharmaceutically acceptable salt thereof, vitamin B₁₂, vitamin B₃, ananti-oxidant vitamin, a beta-blocker, an angiotensin II antagonist, anangiotensin converting enzyme inhibitor, a platelet aggregationinhibitor, or aspirin.
 8. The composition of claim 7, wherein theantihypercholesterolemic agent is a cholesterol biosynthesis inhibitor.9. The composition of claim 8, wherein the cholesterol biosynthesisinhibitor is an hydroxymethylglutaryl CoA reductase inhibitor.
 10. Thecomposition of claim 9, wherein the hydroxymethylglutaryl CoA reductaseinhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, oratorvastatin.
 11. The composition of claim 7, wherein the acyl-coenzymeA cholesterol acyltransferase inhibitor is melinamide.
 12. Thecomposition of claim 7, wherein the cholesterol absorption inhibitor isβ-sitosterol.
 13. The composition of claim 7, wherein the bile acidsequestrant anion exchange resin is cholestyramine, colestipol or adialkylaminoalkyl derivative of a cross-linked dextran.
 14. Thecomposition of claim 7, wherein the fibrate is clofibrate, bezafibrate,fenofibrate, or gemfibrizol.
 15. The composition of claim 7, wherein theanti-oxidant vitamin is vitamin C, vitamin E or beta carotene.
 16. Thecomposition of claim 7, wherein the platelet aggregation inhibitor is afibrinogen receptor antagonist.
 17. The composition of claim 16, whereinthe fibrinogen receptor antagonist is a glycoprotein IIb/IIIa fibrinogenreceptor antagonist.
 18. A pharmaceutical composition, comprising: (a) acompound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, F, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;R^(510, R) ⁵² and R⁵³ are each independently hydrogen, alkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl,heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) one or more of thefollowing: a sulfonylurea, a biguanides, a thiazolidinedione, an insulinsensitizer, dehydroepiandrosterone or its conjugated sulfate ester, anantiglucocorticoid, a TNFα inhibitor, an α-glucosidase inhibitor,pramlintide, an insulin secretogogue, or insulin.
 19. The composition ofclaim 18, wherein the sulfonylurea is chlorpropamide, tolbutamide,acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride,or glipizide.
 20. The composition of claim 18, wherein the biguanide ismetformin.
 21. The composition of claim 18, wherein thethiazolidinedione is ciglitazone, pioglitazone, troglitazone, orrosiglitazone.
 22. The composition of claim 18, wherein the insulinsensitizer is a selective or non-selective activator of PPARα PPARβ orPPAR{tilde over (γ)}.
 23. The composition of claim 18, wherein theα-glucosidase inhibitor is acarbose, miglitol, or voglibose.
 24. Thecomposition of claim 18, wherein the insulin secretogogue isrepaglinide, gliquidone, or nateglinide.
 25. A pharmaceuticalcomposition, comprising: (a) a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and F areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or B and C; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,pertluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) one or more of the following:phenylpropanolamine, phentermine, diethylpropion, mazindol,fenfluramine, dexfenfluramine, phentiramine, a β₃ adrenoceptor agonist,sibutramine, a gastrointestinal lipase inhibitor, a leptin, neuropeptideY, enterostatin, cholecytokinin, bombesin, amylin, a histamine H₃receptor, a dopamine D₂ receptor, melanocyte stimulating hormone,corticotrophin releasing factor, galanin or gamma amino butyric acid.26. The composition of claim 25, wherein the gastrointestinal lipaseinhibitor is orlistat.
 27. A pharmaceutical composition, comprising: (a)a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and F togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) one or more of the following:ursodeoxycholic acid, a corticosteroid, an anti-infective agent, ananti-viral agent, vitamin D, vitamin A, phenobarbital, cholestyramine,UV light, ab antihistamine, an oral opiate receptor antagonist or abiphosphate.
 28. The composition of claim 27, wherein the anti-infectiveagent is rifampin, rifadin, or rimactane.
 29. A method for decreasinghyperglycemia and/or insulin resistance, comprising administering acompound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 30. A method for treatment oramelioration of type II diabetes, comprising administering a compound offormulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituied or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ each independently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 31. A method of treating or amelioratingatherosclerosis, comprising administering a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 32. A method of treating or amelioratingobesity, comprising administering a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 33. A method of treating or amelioratinga disease or disorder selected from hypercholesterolemia,hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy,hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis,gallstone disease, acne vulgaris, acneiform skin conditions, diabetes,Parkinson's disease, cancer, Alzheimer's disease, inflammation,immunological disorders, lipid disorders, obesity, conditionscharacterized by a perturbed epidermal barrier function,hyperlipidernia, cholestasis, peripheral occlusive disease, ischemicstroke, conditions of disturbed differentiation or excess proliferationof the epidermis or mucous membrane, and cardiovascular disorders,comprising administering a pharmaceutical composition of claim
 1. 34. Amethod of treatingr or ameliorating a disease or disorder selected fromhypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia,lipodystrophy, hyperglycemia, diabetes mellitus, dystipidemia,atherosclerosis, gallstone disease, acne vulgaris, acneiform skinconditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease,inflammation, immunological disorders, lipid disorders, obesity,conditions characterized by a perturbed epidermal barrier function,hyperlipidemia, cholestasis, peripheral occlusive disease, isehemicstroke, conditions of disturbed differentiation or excess proliferationof the epidermis or mucous membrane, and cardiovascular disorders,comprising: (a) administering a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or F and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) simultaneously, subsequently, orpreviously administering one or more of the following: anantihyperlipidemic agent, a plasma HDL-raising agent, anantihypercholesterolemic agent, a cholesterol biosynthesis inhibitor, anacyl-coenzyme A:cholesterol acytransferase (ACAT) inhibitor, probucol,raloxifene, nicotinic acid, niacinamide, a cholesterol absorptioninhibitor, a bile acid sequestrant, a low density lipoprotein receptorinducer, clofibrate, fenofibrate, benzofibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, an anti-oxidant vitamin, aβ-blocker, an anti-diabetes agent, an angiotensin II antagonist, anangiotensin converting enzyme inhibitor, a platelet aggregationinhibitor, a fibrinogen receptor antagonist, aspirin or a fibric acidderivative.
 35. A method for decreasing hyperglycemia and/or insulinresistance, comprising administering the pharmaceutical composition ofclaim
 18. 36. A method for decreasing hyperglycemia and/or insulinresistance, comprising: (a) administering a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (I) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsul finyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) subsequently, simultaneously, orpreviously administering one or more of the following: a sulfonylurea, abiguanides, a thiazolidinedione, an insulin sensitizer,dehydroepiandrosterone or its conjugated sulfate ester, anantiglucocorticoid, a TNFα inhibitor, an α-glucosidase inhibitor,pramlintide, an insulin secretogogue, or insulin.
 37. A method fortreatment or amelioration of type II diabetes, comprising administeringa pharmaceutical composition of claim
 18. 38. A method for treatment oramelioration of type II diabetes, comprising: (a) administering acompound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or F and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁶═CR⁷; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triaryl silyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups,substitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) subsequently, simultaneously, orpreviously administering one or more of the following: a sulfonylurea, abiguanides, a thiazolidinedione, an insulin sensitizer,dehydroepiandrosterone or its conjugated sulfate ester, anantiglucocorticoid, a TNFα inhibitor, an α-glucosidase inhibitor,pramlintide, an insulin secretogogue, or insulin.
 39. A method oftreating or ameliorating atherosclerosis, comprising administering apharmaceutical composition of claim
 7. 40. A method of treating orameliorating atherosclerosis, comprising: (a) administering a compoundof formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or F and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, F and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹⁴; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,hetcroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) subsequenstly, simultaneously,or previously administering one or more of the following: anantihyperlipidemic agent, a plasma HDL-raising agent, anantihypercholesterolemic agent, an HMG-CoA synthase inhibitor, asqualene epoxidase inhibitor, a squalene synthetase inhibitor, anacyl-coenzyme A cholesterol acyltransferase inhibitor, probucol,nicotinic acid or a salt thereof, niacinamide, a cholesterol absorptioninhibitor, a bile acid sequestrant anion exchange resin, a low densitylipoprotein receptor inducer, a fibrate, vitamin B₆ or apharmaceutically acceptable salt thereof, vitamin B₁₂, vitamin B₃, ananti-oxidant vitamin, a beta-blocker, an angiotensin II antagonist, anangiotensin converting enzyme inhibitor, a platelet aggregationinhibitor, or aspirin.
 41. A method of treating or ameliorating obesityor complications thereof, comprising administering a pharmaceuticalcomposition of claim
 25. 42. A method of treating or amelioratingobesity or complications thereof, comprising: (a) administering acompound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and C togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R^(13, R) ⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with oneor more substituents each independently selected from Q¹, where Q¹ ishalo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) subsequently, simultaneously, orpreviously administering one or more of the following:phenylpropanolamine, phentermine, diethylpropion, mazindol,fenfluramine, dexfenfluramine, phentiramine, a β₃ adrenoceptor agonist,sibutramine, a gastrointestinal lipase inhibitor, a leptin, neuropeptideY, enterostatin, cholecytokinin, bombesin, amylin, a histamine H₃receptor, a dopamine D₂ receptor, melanocyte stimulating hormone,corticotrophin releasing factor, galanin or gamma amino butyric acid.43. A method of treating or ameliorating cholestasis, comprisingadministering a pharmaceutical composition of claim
 27. 44. A method oftreating or ameliorating cholestasis, comprising: (a) administering acompound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, Eand G are selected from (i) or (ii) as follows: (i) A and G are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³, or A and G togetherform substituted or unsubstituted alkylene, substituted or unsubstitutedazaalkylene, substituted or unsubstituted oxaalkylene, substituted orunsubstituted thiaalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstituted1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene,or substituted or unsubstituted 2-aza-1,3-butadienylene; D and E areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or (ii) A and D; or E and G; together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene,substituted or unsubstituted oxaalkylene, or substituted orunsubstituted thiaalkylene; and the others of A, D, E and G are selectedas in (i); X¹ and X² are each independently selected from O, S, S(═O),S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ andR² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocycl yl, cycloalkylalkyl, heterocycl ylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one ormore substituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; and each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, tnalkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q² groups,which substitute the same atom, together form alkylene; each Q² isindependently unsubstituted or substituted with one or more substituentseach independently selected from alkyl, halo and pseudohalo; R⁵⁰ ishydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹,R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ ishydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹; and (b) subsequently, simultaneously, orpreviously administering one or more of the following: ursodeoxycholicacid, a corticosteroid, an anti-infective agent, an anti-viral agent,vitamin D, vitamin A, phenobarbital, cholestyramine, UV light, abantihistamine, an oral opiate receptor antagonist or a biphosphate. 45.A method of treating or ameliorating a disease or disorder selected fromhypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia,lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia,atherosclerosis, gallstone disease, acne vulgaris, acneiform skinconditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease,inflammation, immunological disorders, lipid disorders, obesity,conditions characterized by a perturbed epidermal barrier function,hyperlipidemia, cholestasis, peripheral occlusive disease, ischemicstroke, conditions of disturbed differentiation or excess proliferationof the epidermis or mucous membrane, cardiovascular disorders, and typeII diabetes, comprising administering a compound of formulae III:

or a pharmaceutically acceptable derivative thereof, wherein: each R⁴ isindependently substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, substituted orunsubstituted guanidino, substituted or unsubstituted isothioureido,halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(=J)R¹³;x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkylmoieties of R⁴ are unsubstituted or substituted with one or moresubstituents each independently selected from Q².
 46. The method ofclaim 45, wherein X² is S and X³ is O.
 47. The method of claim 46,wherein X¹ is S.
 48. The method of claim 47, wherein R¹ is substitutedor unsubstituted alkyl.
 49. The method of claim 48, wherein R² issubstituted or unsubstituted alkyl, or substituted or unsubstitutedaralkyl.
 50. The method of claim 49, wherein R³ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.
 51. Themethod of claim 46, wherein X¹ is CR⁸═CR⁹.
 52. The method of claim 51,wherein R¹ is substituted or unsubstituted alkyl.
 53. The method ofclaim 52, wherein R² is substituted or unsubstituted alkyl, orsubstituted or unsubstituted aralkyl.
 54. The method of claim 53,wherein R³ is substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.
 55. A method of treating or ameliorating adisease or disorder selected from hypercholesterolemia,hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy,hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis,gallstone disease, acne vulgaris, aeneiform skin conditions, diabetes,Parkinson's disease, cancer, Alzheimer's disease, inflammation,immunological disorders, lipid disorders, obesity, conditionscharacterized by a perturbed epidermal barrier function, hyperlipidemia,cholestasis, peripheral occlusive disease, ischemic stroke, conditionsof disturbed differentiation or excess proliferation of the epidermis ormucous membrane, cardiovascular disorders, and type II diabetes,comprising administering a compound of formulae II:

or a pharmaceutically acceptable derivative thereof, wherein: A and Gare each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰,SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; D and E are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; X¹ is S; R¹ and R² are each independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, substituted orunsubstituted heteroarylium, substituted or unsubstitutedheteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² andC(=J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(=J)R¹³; where: R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ andC(=J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl or C(=J)R¹³; J is O, S orNR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl andheteroaryliumalkyl moieties of R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹² and R¹³ are unsubstituted or substituted with one or moresubstituents each independently selected from Q¹, where Q¹ is halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl,heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independentlyhydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl orheterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene,oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independentlyhydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylor heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy,aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 56. Themethod of claim 55, wherein R¹ is substituted or unsubstituted alkyl.57. The method of claim 56, wherein R² is substituted or unsubstitutedalkyl, or substituted or unsubstituted aralkyl.
 58. The method of claim57, wherein R³ is substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.
 59. The method of claim 56, wherein thecompound has formulae VI:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo,pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido,ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring,together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷,R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or moresubstituents each independently selected from R³⁰, where R³⁰ is alkyl,halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 60. The method ofclaim 55, wherein the compound has formulae VII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo,pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylatkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido,ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring,together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷,R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or moresubstituents each independently selected from R³⁰, where R³⁰ is alkyl,halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 61. The method ofclaim 55, wherein the compound has formulae VIII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸, R¹⁹R²⁰ and R²¹ are each independently selected from hydrogen, halo,pseudohalo, hydroxyl, nitric, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylaryl silyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido,ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ which substitute adjacent carbons on the ring, togetherform alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹,R²⁰ and R²¹ are unsubstituted or substituted with one or moresubstituents each independently selected from R³⁰, where R³⁰ is alkyl,halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 62. The method ofclaim 55, wherein the compound has formulae IX:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo,pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiaryl silyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido,ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ which substitute adjacent carbons on the ring, togetherform alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹,R²⁰ and R²¹ are unsubstituted or substituted with one or moresubstituents each independently selected from R³⁰, where R³⁰ is alkyl,halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.